16-ene-vitamin D derivatives

ABSTRACT

A vitamin D derivative of general formula (1):                    
     wherein X represents an oxygen or sulfur atom, R 11  represents a saturated or unsaturated aliphatic hydrocarbon group which may be substituted by a hydroxyl group or a protected hydroxyl group, or a —COR 12  group where R 12  represents an alkyl, aryl or alkoxy group, R 2  represents —OR 9  or a hydrogen atom, and R 9  and R 10  each represent a hydrogen atom or a hydroxyl group.

CROSS REFERENCE TO RELATED APPLICATION

The present application is the national stage under 35 U.S.C. 371 ofPCT/JP97/04715, filed Dec. 19, 1997.

TECHNICAL FIELD

The present invention relates to novel vitamin D derivatives with highbinding ability to vitamin D receptors and weak hypercalcemic activity,useful compounds as pharmaceutical agents such as antitumor agents,antirheumatic agents, etc., and novel synthetic intermediates which areuseful for synthesis of said compounds.

BACKGROUND ART

Activated vitamins D₃ including 1α, 25-dihydroxy-vitamin D₃ are known tohave many physiological activities such as calcium catabolismregulation, growth inhibition and differentiation induction of tumorcells, immunoregulation. However, some activated vitamins D₃disadvantageously cause hypercalcemia during long-term and continuousadministration so that they are not suitable for use as antitumoragents, antirheumatic agents or the like. Thus, a number of vitamin Dderivatives have been synthesized and examined for the purpose ofseparating activities of these vitamins D.

For example, JPA No. 267550/86 discloses1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutyloxy)-9,10-secopregna-5,7,10(19)-triene and JPA No. 330714/95 discloses a vitamin D derivativesubstituted by a sulfur atom at the 22-position.

Various vitamin D derivatives having a double bond at the 16-positionare described in JPA No. 9861/90, JPA No. 17019/91, JPA No. 188159/95,JPA No. 40975/94, JPA No. 179418/95, U.S. Pat. No. 5,087,619 and U.S.Pat. No. 5,145,846, etc. However, none of these compounds are said tohave weak hypercalcemic activity.

Many of these known vitamin D compounds have high binding ability tovitamin D receptors but strong hypercalcemic activity, or weakhypercalcemic activity but unsatisfactory binding ability to vitamin Dreceptors. Therefore, it would be desirable to develop promisingcompounds with high binding ability to vitamin D receptors and weakhypercalcemic activity.

DISCLOSURE OF INVENTION

As a result of careful studies of compounds with high binding ability tovitamin D receptors and weak hypercalcemic activity in view of the aboveproblems, we found that compounds of general formula (1):

wherein X represents an oxygen or sulfur atom, R₁₁ represents asaturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group or a protected hydroxyl group, or a—COR₁₂ group where R₁₂ represents an alkyl, aryl or alkoxy group, R₂represents —OR₉ or a hydrogen atom, and R₉ and R₁₀ may be the same ordifferent and each represent a hydrogen atom or a protecting group, havehigh binding ability to vitamin D receptors and weak hypercalcemicactivity, and thus accomplished the present invention.

According to one aspect of the present invention, vitamin D derivativesof general formula (1):

wherein X represents an oxygen or sulfur atom, R₁₁ represents asaturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group or a protected hydroxyl group, or a—COR₁₂ group where R₁₂ represents an alkyl, aryl or alkoxy group, R₂represents —OR₉ or a hydrogen atom, and R₉ and R₁₀ may be the same ordifferent and each represent a hydrogen atom or a protecting group areprovided.

In general formula (1), R₂ is preferably —OR₉.

In general formula (1), R₁₁ is preferably a saturated C1-C15 aliphatichydrocarbon group which may be substituted by a hydroxyl group.

In general formula (1), R₁₁ is preferably an unsaturated C2-C15aliphatic hydrocarbon group which may be substituted by a hydroxylgroup.

In general formula (1), R₁₁ is preferably a group (2):

wherein R₃ and R₄ may be the same or different and each represent ahydrogen atom or a hydroxyl group, or are combined to represent ═O,provided that R₃ and R₄ can not be a hydroxyl groups simultaneously, R₅and R₆ each represent a hydrogen atom or a hydroxyl group, but R₆ cannot be a hydroxyl group simultaneously with R₃ or R₄, m represents aninteger of 1 to 4, and n represents an integer of 0 to 2; or a group(3):

wherein R₅ and R₆ may be the same or different and each represent ahydrogen atom or a hydroxyl group, R₇ and R₈ each represent a hydrogenatom or are combined to represent a covalent bond, p represents aninteger of 1 to 3, and q represents an integer of 0 to 2.

In general formula (1), R₁₁ is especially preferably a3-hyroxy-3-methylbutyl group.

In an embodiment of compounds represented by general formula (1), the20-position is in S-configuration.

In another embodiment of compounds represented by general formula (1),the 20-position is in R-configuration.

Specific examples of compounds represented by general formula (1)include1,3-dihydroxy-20-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.Sterically defined examples of this compound include1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraeneand1α,3β-dihydroxy-20(R)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.

Other specific examples of compounds represented by general formula (1)include1α,3β-dihydroxy-20(R)-((E)-4-hydroxy-4-methyl-2-pentenylthio)-9,10-secopregna-5,7,10(19),16-tetraeneand1α,3β-dihydroxy-20(R)-((E)-4-ethyl-4-hydroxy-2-hexenylthio)-9,10-secopregna-5,7,10(19),16-tetraene.

Other specific examples of compounds represented by general formula (1)include1α,3β-dihydroxy-20(S)-(2-hydroxy-2-methylpropylthio)-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(R)-(2-hydroxy-2-methylpropyl-thio)-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(S)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene;and1α,3β-dihydroxy-20(R)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.

According to another aspect of the present invention, compounds ofgeneral formula (4):

wherein X represents an oxygen or sulfur atom, R₁₁ represents asaturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group or a protected hydroxyl group, or a—COR₁₂ group where R₁₂ represents an alkyl, aryl or alkoxy group, and R₉and R₁₀ may be the same or different and each represent a hydrogen atomor a protecting group are provided.

In general formula (4), R₁₁ is preferably a saturated C1-C15 aliphatichydrocarbon group which may be substituted by a hydroxyl group.

In general formula (4), R₁₁ is preferably an unsaturated C2-C15aliphatic hydrocarbon group which may be substituted by a hydroxylgroup.

In general formula (4), R₁₁ is preferably a group (2):

wherein R₃ and R₄ may be the same or different and each represent ahydrogen atom or a hydroxyl group, or are combined to represent ═O,provided that R₃ and R₄ can not be a hydroxyl group simultaneously, R₅and R₆ each represent a hydrogen atom or a hydroxyl group, but R₆ cannot be a hydroxyl group simultaneously with R₃ or R₄, m represents aninteger of 1 to 4, and n represents an integer of 0 to 2; or a group(3):

wherein R₅ and R₆ may be the same or different and each represent ahydrogen atom or a hydroxyl group, R₇ and R₈ each represent a hydrogenatom or are combined to represent a covalent bond, p represents aninteger of 1 to 3, and q represents an integer of 0 to 2.

In general formula (4), R₁₁ is especially preferably a3-hyroxy-3-methylbutyl group.

According to another aspect of the present invention, compounds ofgeneral formula (24):

wherein R₉ and R₁₀ may be the same or different and each represent ahydrogen atom or a protecting group are provided.

According to still another aspect of the present invention, compounds ofgeneral formula (5):

wherein R₉ and R₁₀ may be the same or different and each represent ahydrogen atom or a protecting group, and the conjugated double bond inthe formula may be protected by a protecting group are provided.

According to still another aspect of the present invention, compounds ofgeneral formula (6):

wherein R₉ and R₁₀ may be the same or different and each represent ahydrogen atom or a protecting group are provided.

According to still another aspect of the present invention, compounds ofgeneral formula (7):

wherein R₉ and R₁₀ may be the same or different and each represent ahydrogen atom or a protecting group are provided.

According to still another aspect of the present invention, a processfor preparing a vitamin D derivative of general formula (1):

wherein X represents an oxygen or sulfur atom, R₁₁ represents asaturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group or a protected hydroxyl group, or a—COR₁₂ group where R₁₂ represents an alkyl, aryl or alkoxy group, R₂represents —OR₉ or a hydrogen atom, and R₉ and R₁₀ may be the same ordifferent and each represent a hydrogen atom or a hydroxyl group isprovided, which process comprises subjecting a compound of generalformula (4a):

wherein X represents an oxygen or sulfur atom, R₁ represents a saturatedor unsaturated aliphatic hydrocarbon group which may be substituted by ahydroxyl group or a protected hydroxyl group, or a —COR₁₂ group whereR₁₂ represents an alkyl, aryl or alkoxy group, and R₉ and R₁₀ may be thesame or different and each represent a hydrogen atom or a protectinggroup, to photoreaction, thermal isomerization and deprotection.

According to still another aspect of the present invention,pharmaceutical agents comprising a vitamin D derivative of generalformula (1) are provided.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 is a graph showing assay results of the ionized calcium level inblood after administration of an activated vitamin D₃ or vitamin D₃derivatives.

FIG. 2 is a graph showing assay results of the ionized calcium level inblood after administration of an activated vitamin D₃ or vitamin D₃derivatives.

FIG. 3 is a graph showing assay results of the ionized calcium level inblood after administration of an activated vitamin D₃ or vitamin D₃derivatives.

FIG. 4 is a graph showing evaluation test results of thedifferentiation-inducing activity of an activated vitamin D₃ or vitaminD₃ derivatives.

FIG. 5 is a graph showing evaluation test results of thedifferentiation-inducing activity of an activated vitamin D₃ or vitaminD₃ derivatives.

FIG. 6 is a graph showing evaluation test results of thedifferentiation-inducing activity of an activated vitamin D₃ or vitaminD₃ derivatives.

THE MOST PREFERRED EMBODIMENTS OF INVENTION

Terms as used herein have the following meanings unless otherwisespecified.

The saturated aliphatic hydrocarbon group generally means a straight orbranched alkyl group containing 1 to 15 carbon atoms, such as methyl,ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl and t-butyl groupsas well as pentyl, hexyl, heptyl, octyl, nonyl and decanyl groups,preferably 3-methylbutyl, 3-ethylpentyl, 4-methylpentyl,3-(n-propyl)hexyl, 4-ethylhexyl, 5-methylhexyl, 6-methylheptyl,5-ethylheptyl and 4-(n-propyl)heptyl groups or the like, more preferably3-methylbutyl, 3-ethylpentyl and 4-methylpentyl groups or the like.

The unsaturated aliphatic hydrocarbon group generally means a straightor branched alkenyl or alkynyl group containing 2 to 15 carbon atoms,such as 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl,4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 2-propynyl, 2-butynyl,3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 5-heptynyl and6-heptynyl groups, in which any hydrogen atom may be substituted by oneor more alkyl groups as mentioned above, and the double bond may be ineither cis- or trans-configuration. Preferred are 4-methyl-2-pentynyl,4-ethyl-2-hexynyl, 4-methyl-2-pentenyl and 4-ethyl-2-hexenyl groups orthe like.

The saturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group means said saturated or unsaturatedhydrocarbon group in which any hydrogen atom may be substituted by oneor more hydroxyl groups such as 0, 1, 2, 3 hydroxyl groups, preferably 1or 2 hydroxyl groups, more preferably one hydroxyl group. Specificexamples other than the aliphatic hydrocarbon groups as mentioned aboveinclude saturated aliphatic hydrocarbon groups such as2-hydroxy-2-methylpropyl, 3-hydroxy-2-methylpropyl,2,3-dihydroxy-2-methylpropyl, 2-ethyl-2-hydroxybutyl,2-ethyl-3-hydroxybutyl, 2-ethyl-2,3-dihydroxybutyl,2-hydroxy-2-(n-propyl)pentyl, 3-hydroxy-2-(n-propyl)pentyl,2,3-dihydroxy-2-(n-propyl)pentyl, 2-hydroxy-3-methylbutyl,3-hydroxy-3-methylbutyl, 4-hydroxy-3-methylbutyl,2,3-dihydroxy-3-methylbutyl, 2,4-dihydroxy-3-methylbutyl,3,4-dihydroxy-3-methylbutyl, 3-ethyl-2-hydroxypentyl,3-ethyl-3-hydroxypentyl, 3-ethyl-4-hydroxypentyl,3-ethyl-2,3-dihydroxypentyl, 3-ethyl-2,4-dihydroxypentyl,3-ethyl-3,4-dihydroxypentyl, 2-hydroxy-3-(n-propyl)hexyl,3-hydoxy-3-(n-propyl)hexyl, 4-hydroxy-3-(n-propyl)hexyl,2,3-dihydroxy-3-(n-propyl)hexyl, 2,4-dihydroxy-3-(n-propyl)hexyl,3,4-dihydroxy-3-(n-propyl)hexyl, 3-hydroxy-4-methylpentyl,4-hydroxy-4-methylpentyl, 5-hydroxy-4-methylpentyl,3,4-dihydroxy-4-methylpentyl, 3,5-dihydroxy-4-methylpentyl,4,5-dihydroxy-4-methylpentyl, 4-ethyl-3-hydroxyhexyl,4-ethyl-4-hydroxyhexyl, 4-ethyl-5-hydroxyhexyl,4-ethyl-3,4-dihydroxyhexyl, 4-ethyl-3,5-dihydroxyhexyl,4-ethyl-4,5-dihydroxyhexyl, 3-hydroxy-4-(n-propyl)heptyl,4-hydroxy-4-(n-propyl)heptyl, 5-hydroxy-4-(n-propyl)heptyl,3,4-dihydroxy-4-(n-propyl)heptyl, 3,5-dihydroxy-4-(n-propyl)heptyl,4,5-dihydroxy-4-(n-propyl)heptyl, 4-hydroxy-5-methylhexyl,5-hydroxy-5-methylhexyl, 6-hydroxy-5-methylhexyl,4,5-dihydroxy-5-methylhexyl, 4,6-dihydroxy-5-methylhexyl,5,6-dihydroxy-5-methylhexyl, 5-ethyl-4-hydroxyheptyl,5-ethyl-5-hydroxyheptyl, 5-ethyl-6-hydroxyheptyl,5-ethyl-4,5-dihydroxyheptyl, 5-ethyl-4,6-dihydroxyheptyl,5-ethyl-5,6-dihydroxyheptyl, 4-hydroxy-5-(n-propyl)octyl,5-hydroxy-5-(n-propyl)octyl, 6-hydroxy-5-(n-propyl)octyl,4,5-dihydroxy-5-(n-propyl)octyl, 4,6-dihydroxy-5-(n-propyl)octyl,5,6-dihydroxy-5-(n-propyl)octyl, 5-hydroxy-6-methylheptyl,6-hydroxy-6-methylheptyl, 7-hydroxy-6-methylheptyl,5,6-dihydroxy-6-methylheptyl, 5,7-dihydroxy-6-methylheptyl,6,7-dihydroxy-6-methylheptyl, 6-ethyl-5-hydroxyoctyl,6-ethyl-6-hydroxyoctyl, 6-ethyl-7- hydroxyoctyl, 6-ethyl-5,6-hydroxyoctyl, 6-ethyl-5,7-hydroxyoctyl, 6-ethyl-6,7-hydroxyoctyl,5-hydroxy-6-(n-propyl)nonyl, 6-hydroxy-6-(n-propyl)nonyl,7-hydroxy-6-(n-propyl)nonyl, 5,6-dihydroxy-6-(n-propyl)nonyl,5,7-dihydroxy-6-(n-propyl)nonyl, 6,7-dihydroxy-6-(n-propyl)nonyl groups;and 4-hydroxy-4-methyl-2-pentenyl, 5-hydroxy-4-methyl-2-pentenyl,4,5-dihydroxy-4-methyl-2-pentenyl, 4-ethyl-4-hydroxy-2-hexenyl,4-ethyl-5-hydroxy-2-hexenyl, 4-ethyl-4,5-dihydroxy-2-hexenyl,4-hydroxy-4-(n-propyl)-2-heptenyl, 5-hydroxy-4-(n-propyl)-2-heptenyl,4,5-dihydroxy-4-(n-propyl)-2-heptenyl, 5-hydroxy-5-methyl-3-hexenyl,6-hydroxy-5-methyl-3-hexenyl, 5,6-dihydroxy-5-methyl-3-hexenyl,5-ethyl-5-hydroxy-3-heptenyl, 5-ethyl-6-hydroxy-3-heptenyl,5-ethyl-5,6-dihydroxy-3-heptenyl, 5-hydroxy-5-(n-propyl)-3-octenyl,6-hydroxy-5-(n-propyl)-3-octenyl, 5,6-dihydroxy-5-(n-propyl)-3-octenyl,4-hydroxy-5-methyl-2-hexenyl, 5-hydroxy-5-methyl-2-hexenyl,6-hydroxy-5-methyl-2-hexenyl, 4,5-dihydroxy-5-methyl-2-hexenyl,4,6-dihydroxy-5-methyl-2-hexenyl, 5,6-dihydroxy-5-methyl-2-hexenyl,5-ethyl-4-hydroxy-2-heptenyl, 5-ethyl-5-hydroxy-2-heptenyl,5-ethyl-6-hydroxy-2-heptenyl, 5-ethyl-4,5-dihydroxy-2-heptenyl,5-ethyl-4,6-dihydroxy-2-heptenyl, 5-ethyl-5,6-dihydroxy-2-heptenyl,4-hydroxy-5-(n-propyl)-2-octenyl, 5-hydroxy-5-(n-propyl)-2-octenyl,6-hydroxy-5-(n-propyl)-2-octenyl, 4,5-dihydroxy-5-(n-propyl)-2-octenyl,4,6-dihydroxy-5-(n-propyl)-2-octenyl,5,6-dihydroxy-5-(n-propyl)-2-octenyl, 6-hydroxy-6-methyl-4-heptenyl,7-hydroxy-6-methyl-4-heptenyl, 6,7-dihydroxy-6-methyl-4-heptenyl,6-ethyl-6-hydroxy-4-octenyl, 6-ethyl-7-hydroxy-4-octenyl,6-ethyl-6,7-dihydroxy-4-octenyl, 6-hydroxy-6-(n-propyl)-4-nonenyl,7-hydroxy-6-(n-propyl)-4-nonenyl, 6,7-dihydroxy-6-(n-propyl)-4-nonenyl,5-hydroxy-6-methyl-3-heptenyl, 6-hydroxy-6-methyl-3-heptenyl,7-hydroxy-6-methyl-3-heptenyl, 5,6-dihydroxy-6-methyl-3-heptenyl,5,7-dihydroxy-6-methyl-3-heptenyl, 6,7-dihydroxy-6-methyl-3-heptenyl,6-ethyl-5-hydroxy-3-octenyl, 6-ethyl-6-hydroxy-3-octenyl,6-ethyl-7-hydroxy-3-octenyl, 6-ethyl-5,6-dihydroxy-3-octenyl,6-ethyl-5,7-dihydroxy-3-octenyl, 6-ethyl-6,7-dihydroxy-3-octenyl,5-hydroxy-6-(n-propyl)-3-nonenyl, 6-hydroxy-6-(n-propyl)-3-nonenyl,7-hydroxy-6-(n-propyl)-3-nonenyl, 5,6-dihydroxy-6-(n-propyl)-3-nonenyl,5,7-dihydroxy-6-(n-propyl)-3-nonenyl,6,7-dihydroxy-6-(n-propyl)-3-nonenyl, 5-hydroxy-6-methyl-2-heptenyl,6-hydroxy-6-methyl-2-heptenyl, 7-hydroxy-6-methyl-2-heptenyl,5,6-dihydroxy-6-methyl-2-heptenyl, 5,7-dihydroxy-6-methyl-2-heptenyl,6,7-dihydroxy-6-methyl-2-heptenyl, 6-ethyl-5-hydroxy-2-octenyl,6-ethyl-6-hydroxy-2-5 octenyl, 6-ethyl-7-hydroxy-2-octenyl,6-ethyl-5,6-dihydroxy-2-octenyl, 6-ethyl-5,7-dihydroxy-2-octenyl,6-ethyl-6,7-dihydroxy-2-octenyl, 5-hydroxy-6-(n-propyl)-2-nonenyl,6-hydroxy-6-(n-propyl)-2-nonenyl, 7-hydroxy-6-(n-propyl)-2-nonenyl,5,6-dihydroxy-6-(n-propyl)-2-nonenyl,5,7-dihydroxy-6-(n-propyl)-2-nonenyl,6,7-dihydroxy-6-(n-propyl)-2-nonenyl, 4-hydroxy-4-methyl-2-pentynyl,5-hydroxy-4-methyl-2-pentynyl, 4,5-dihydroxy-4-methyl-2-pentynyl,4-ethyl-4-hydroxy-2-hexynyl, 4-ethyl-5-hydroxy-2-hexynyl,4-ethyl-4,5-dihydroxy-2-hexynyl, 4-hydroxy-4-(n-propyl)-2-15 heptynyl,5-hydroxy-4-(n-propyl)-2-heptynyl,4,5-dihydroxy-4-(n-propyl)-2-heptynyl, 5-hydroxy-5-methyl-3-hexynyl,6-hydroxy-5-methyl-3-hexynyl, 5,6-dihydroxy-5-methyl-3-hexynyl,5-ethyl-5-hydroxy-3-heptynyl, 5-ethyl-6-hydroxy-3-heptynyl,5-ethyl-5,6-dihydroxy-3-heptynyl, 5-hydroxy-5-(n-propyl)-3-octynyl,6-hydroxy-5-(n-propyl)-3-octynyl, 5,6-dihydroxy-5-(n-propyl)-3-octynyl,4-hydroxy-5-methyl-2-hexynyl, 5-hydroxy-5-methyl-2-hexynyl,6-hydroxy-5-methyl-2-hexynyl, 4,5-dihydroxy-5-methyl-2-hexynyl,4,6-dihydroxy-5-methyl-2-hexynyl, 5,6-dihydroxy-5-methyl-2-hexynyl,5-ethyl-4-hydroxy-2-heptynyl, 5-ethyl-5-hydroxy-2-heptynyl,5-ethyl-6-hydroxy-2-heptynyl, 5-ethyl-4,5-dihydroxy-2-heptynyl,5-ethyl-4,6-dihydroxy-2-heptynyl, 5-ethyl-5,6-dihydroxy-2-heptynyl,4-hydroxy-5-(n-propyl)-2-octynyl, 5-hydroxy-5-(n-propyl)-2-octynyl,6-hydroxy-5-(n-propyl)-2-octynyl, 4,5-dihydroxy-5-(n-propyl)-2-octynyl,4,6-dihydroxy-5-(n-propyl)-2-octynyl,5,6-dihydroxy-5-(n-propyl)-2-octynyl, 6-hydroxy-6-methyl-4-heptynyl,7-hydroxy-6-methyl-4-heptynyl, 6,7-dihydroxy-6-methyl-4-heptynyl,6-ethyl-6-hydroxy-4-octynyl, 6-ethyl-7-hydroxy-4-octynyl,6-ethyl-6,7-dihydroxy-4-octynyl, 6-hydroxy-6-(n-propyl)-4-nonynyl,7-hydroxy-6-(n-propyl)-4-nonynyl, 6,7-dihydroxy-6-(n-propyl)-4-nonynyl,5-hydroxy-6-methyl-3-heptynyl, 6-hydroxy-6-methyl-3-heptynyl,7-hydroxy-6-methyl-3-heptynyl, 5,6-dihydroxy-6-methyl-3-heptynyl,5,7-dihydroxy-6-methyl-3-heptynyl, 6,7-dihydroxy-6-methyl-3-heptynyl,6-ethyl-5-hydroxy-3-octynyl, 6-ethyl-6-hydroxy-3-octynyl,6-ethyl-7-hydroxy-3-octynyl, 6-ethyl-5,6-dihydroxy-3-octynyl,6-ethyl-5,7-dihydroxy-3-octynyl, 6-ethyl-6,7-dihydroxy-3-octynyl,5-hydroxy-6-(n-propyl)-3-nonynyl, 6-hydroxy-6-(n-propyl)-3-nonynyl,7-hydroxy-6-(n-propyl)-3-nonynyl, 5,6-dihydroxy-6-(n-propyl)-3-nonynyl,5,7-dihydroxy-6-(n-propyl)-3-nonynyl,6,7-dihydroxy-6-(n-propyl)-3-nonynyl, 5-hydroxy-6-methyl-2-heptynyl,6-hydroxy-6-methyl-2-heptynyl, 7-hydroxy-6-methyl-2-heptynyl,5,6-dihydroxy-6-methyl-2-heptynyl, 5,7-dihydroxy-6-methyl-2-heptynyl,6,7-dihydroxy-6-methyl-2-heptynyl, 6-ethyl-5-hydroxy-2-octynyl,6-ethyl-6-hydroxy-2-octynyl, 6-ethyl-7-hydroxy-2-octynyl,6-ethyl-5,6-dihydroxy-2-octynyl, 6-ethyl-5,7-dihydroxy-2-octynyl,6-ethyl-6,7-dihydroxy-2-octynyl, 5-hydroxy-6-(n-propyl)-2-nonynyl,6-hydroxy-6-(n-propyl)-2-nonynyl, 7-hydroxy-6-(n-propyl)-2-nonynyl,5,6-dihydroxy-6-(n-propyl)-2-nonynyl,5,7-dihydroxy-6-(n-propyl)-2-nonynyl,6,7-dihydroxy-6-(n-propyl)-2-nonynyl groups or the like, preferably3-hydroxy-3-methylbutyl, 4-hydroxy-3-methylbutyl,3,4-dihydroxy-3-methylbutyl, 3-ethyl-3-hydroxypentyl,3-ethyl-4-hydroxypentyl, 3-ethyl-3,4-dihydroxypentyl,4-hydroxy-4-methylpentyl, 5-hydroxy-4-methylpentyl,4,5-dihydroxy-4-methylpentyl, 4-ethyl-4-hydroxyhexyl,4-ethyl-5-hydroxyhexyl, 4-ethyl-4,5-dihydroxyhexyl,4-hydroxy-4-methyl-2-pentenyl, 5-hydroxy-4-methyl-2-pentenyl,4,5-dihydroxy-4-methyl-2-pentenyl, 4-ethyl-4-hydroxy-2-hexenyl,4-ethyl-5-hydroxy-2-hexenyl, 4-ethyl-4,5-dihydroxy-2-hexenyl,4-hydroxy-4-methyl-2-pentynyl, 5-hydroxy-4-methyl-2-pentynyl,4,5-dihydroxy-4-methyl-2-pentynyl, 4-ethyl-4-hydroxy-2-hexynyl,4-ethyl-5-hydroxy-2-hexynyl, 4-ethyl-4,5-dihydroxy-2-hexynyl groups orthe like.

As used herein, the alkyl group generally means a straight or branchedalkyl group containing 1 to 15, preferably 1 to 8 carbon atoms; the arylgroup generally means an aryl group containing 6 to 20, preferably 6 to14 carbon atoms; and the alkoxy group generally means a straight orbranched alkoxy group containing 1 to 15, preferably 1 to 8 carbonatoms.

The protecting group includes acyl, substituted silyl and substitutedalkyl groups or the like, preferably acyl and substituted silyl groups.

The acyl group means a substituted carbonyl group where the substituenton the carbonyl group includes a hydrogen atom, an optionallysubstituted lower alkyl group, an optionally substituted aryl group, anoptionally substituted lower alkyloxy group, an optionally substitutedaryloxy group, an optionally substituted aralkyloxy group or the like.The acyl group preferably includes a formyl group, a lower alkylcarbonylgroup, an optionally substituted phenylcarbonyl group, a loweralkyloxycarbonyl group, an optionally substituted phenylalkyloxycarbonylgroup or the like, more preferably formyl, acetyl, propionyl, butyryl,pivaloyl, benzoyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl,benzyloxycarbonyl groups or the like.

The substituted silyl group means a silyl group substituted by a loweralkyl group which may have one or more substituents or an optionallysubstituted aryl group or the like, preferably a tri-substituted silylgroup. Preferred examples of the substituted silyl group includetrimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldiphenylsilyl,t-butyldimethylsilyl groups or the like.

The substituted alkyl group means an alkyl group substituted by one ormore substituents preferably including an optionally substitutedalkyloxy group and an optionally substituted aryl group, especially anoptionally substituted alkyloxy group. The alkyl group substituted by anoptionally substituted alkyloxy group such as an alkyloxy groupincludes, for example, methoxymethyl, 2-methoxyethoxy-methyl andtetrahydropyran-2-yl groups or the like. Examples of the substituentinclude halogen atoms and cyano, nitro, amino, hydroxyl, alkyl,alkyloxy, acyloxy and sulfonyl groups or the like.

Compounds of general formula (1) of the present invention wherein X is asulfur atom can be prepared from, for example, a compound of formula (8)described in JPA No. 330714/95 as shown by the following scheme:

wherein TBS represents a t-butyldimethylsilyl group, R₁₂ represents analkyl, aryl or alkoxy group, R_(1a) represents a saturated orunsaturated aliphatic hydrocarbon group which may be substituted by ahydroxyl group or a protected hydroxyl group, and R_(1b) represents asaturated or unsaturated aliphatic hydrocarbon group substituted by ahydroxyl group.

In the above scheme, the compound of general formula (8) obtained by thesame procedure as described in JPA No. 330714/95 may be reacted with analkyl halothioformate or an aryl halothioformate in an appropriatesolvent in the presence of a base to give a compound of general formula(9) through an o-alkyl thiocarbonate or alkyl dithiocarbonate (step 1).

The alkyl halothioformate or aryl halothioformate used in the above step1 includes, for example, phenyl chlorothionoformate, tolylchlorothionoformate, 4-tert-butylphenyl chlorothionoformate,4-fluorophenyl chlorothionoformate, 3-chlorophenyl chlorothionoformate,4-chlorophenyl chlorothionoformate, 3,4-dichlorophenylchlorothionoformate, 2,4,6-trichlorophenyl chlorothionoformate,pentafluorophenyl chlorothionoformate, methyl chlorodithioformate, ethylchlorodithioformate, isopropyl chlorodithioformate, phenylchlorodithioformate, tolyl chlorodithioformate, 2,4,6-trimethylphenylchlorodithioformate, 4-fluorophenyl chlorodithioformate,pentafluorophenyl chlorodithioformate, 2-chlorophenylchlorodithioformate, 3-chlorophenyl chlorodithioformate, 4-chlorophenylchlorodithioformate, 2,4,5-trichlorophenyl chlorodithioformate,pentachlorophenyl chlorodithioformate, 4-methoxyphenylchlorodithioformate, 4-cyanophenyl chlorodithioformate, 4-nitrophenylchlorodithioformate or the like, preferably phenyl chlorothionoformate,tolyl chlorothionoformate, 4-tert-butylphenyl chlorothionoformate,4-fluorophenyl chlorothionoformate, 4-chlorophenyl chlorothionoformate,2,4,6-trichlorophenyl chlorothionoformate, pentafluorophenylchlorothionoformate, phenyl chlorodithioformate or the like, morepreferably phenyl chlorothionoformate.

Suitable solvents for use in the above step 1 include hydrocarbon-,ether-, halogen-based solvents or the like, such as benzene, toluene,diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, dichloromethane,chloroform, carbon tetrachloride, preferably dichloromethane, toluene orthe like, more preferably dichloromethane.

Suitable bases for use in the above step 1 include pyridine compounds,amine compounds, imidazole compounds, alkali metal hydroxides, metalhydrides, alkali metal compounds, metal amides or the like, such aspyridine, collidine, lutidine, 2,6-di-tert-butylpyridine,4-methyl-2,6-di-tert-butylpyridine, 4-dimethylaminopyridine,triethylamine, diisopropylethylamine, imidazole, sodium hydroxide,potassium hydroxide, sodium hydride, potassium hydride, methyl lithium,n-butyl lithium, ethyl magnesium bromide, lithium diisopropylamide,lithium bistrimethyl-silylamide, preferably pyridine, collidine,lutidine, 2,6-di-tert-butylpyridine, 4-methyl-2,6-di-tert-butylpyridine,4-dimethylaminopyridine, triethylamine, diisopropylethylamine, morepreferably pyridine.

The reaction temperature of the above step 1 is in the range from 0 to100° C., preferably room temperature, though it is not specificallylimited so far as the reaction proceeds. This reaction allows selectivesynthesis of thiol carbonates having 20S configuration from 16α-OHisomers and thiol carbonates having 20R configuration from 16β-OHisomers, respectively.

The compound of general formula (9) forms a part of the intermediate ofgeneral formula (4).

The compound of general formula (9) may be subjected to alkalisolvolysis and S-alkylation to give a compound of general formula (10)in which a side chain has been introduced (step 2).

The base used for the alkali solvolysis and S-alkylation in the abovestep 2 includes lithium hydroxide, sodium hydroxide, potassiumhydroxide, sodium methoxide, potassium tert-butoxide or the like,preferably sodium hydroxide, potassium hydroxide, sodium methoxide orthe like. The reaction can be carried out in water or an alcoholicsolvent such as methanol, ethanol, propanol, butanol, alone or mixedwith an etheric solvent such as diethyl ether, tetrahydrofuran,1,2-dimethoxyethane, 1,4-dioxane, diglyme, etc.

Suitable alkylating agents include compounds of general formula (13)corresponding to the side chain:

Y—R_(1a)  (13)

wherein Y represents a halogen atom or a leaving group such as mesyloxy,tosyloxy, trifluoromethanesulfonyloxy, and R_(1a) has the same meaningas above, or epoxides such as isobutyrene oxide,1,2-epoxy-2-ethylbutane, 1,2-epoxy-3-ethylbutane,1,2-epoxy-3-ethylpentane.

The compound of general formula (10) forms a part of the intermediate ofgeneral formula (4).

Suitable compounds of general formula (13) include alkylating agentscorresponding to R₁ in the compound of general formula (1) of thepresent invention, such as 4-bromo-2-methyl-2-butanol,1-bromo-4-methyl-4-triethylsilyloxypentane, 6-bromo-2-methyl-2-hexanol,5-bromo-3-ethyl-3-pentanol, 6-bromo-3-ethyl-3-hexanol.

The reaction of the above step 2 is carried out at a temperature of −40to 100° C., preferably 0 to 50° C., more preferably room temperature.

The compound of general formula (10) can be converted into a compound ofgeneral formula (11) by a conventional deprotection procedure (step 3).

Suitable reagents for use in the reaction of the above step 3 includehydrochloric acid, acidic ion exchange resin, tetrabutylammoniumfluoride, hydrogen fluoride/pyridine, hydrogen fluoride/triethylamine,hydrofluoric acid, preferably tetrabutylammonium fluoride.

Suitable solvents for use in the above step 3 typically include ethericsolvents, preferably tetrahydrofuran.

The reaction temperature ranges from room temperature to 65° C.,depending on the type of the substrate.

The deprotected compound of general formula (11) also forms a part ofthe intermediate of general formula (4).

The compound of general formula (11) may be subjected to photoreactionand thermal isomerization to give a compound (12) which corresponds to acompound of general formula (1) of the present invention wherein Xrepresents a sulfur atom and R₁ represents a saturated aliphatichydrocarbon group which may be substituted by a hydroxyl group (step 4).The photoreaction and thermal isomerization here can be carried out by aconventional procedure.

The compound of general formula (9) which has not been deprotected maybe subjected to photoreaction and thermal isomerization to give acompound of general formula (1) wherein the hydroxyl group is protected.The order of steps 1, 2, 3 and 4 is not specifically limited, but step 2can not precede step 1. The process can not be carried out in the orderof steps 4→3→1→2. When the side chain has a protecting group, step 3 canbe carried out if desired.

Compounds of general formula (1) of the present invention wherein X isan oxygen atom can be obtained from, for example, a known compound (14)described in JPA No. 330714/95 as shown by the following scheme:

wherein TBS represents a t-butyldimethylsilyl group.

In the above scheme, the compound of formula (14) obtained by the sameprocedure as described in JPA No. 330714/95 may be oxidized to give acompound of formula (15) (step 1).

Suitable oxidizing agents for use in the above step 1 includem-chloroperbenzoic acid, magnesium monoperoxyphthalate, hydrogenperoxide or the like, preferably m-chloroperbenzoic acid.

Suitable solvents for use in the above step 1 include toluene, benzene,dichloromethane, chloroform, carbon tetrachloride or the like,preferably toluene or dichloromethane. The reaction may be carried outin the presence of a neutralizing agent such as sodium bicarbonate orsodium dihydrogenphosphate in the reaction system.

The reaction temperature of the above step 1 is −78 to 110° C.,preferably −40° C. to room temperature.

The compound of formula (15) can be deprotected by a conventionalprocedure described in, for example, Journal of Organic Chemistry, 57,5019 (1992), to give a compound of formula (16) (step 2).

The compound of formula (15) or (16) forms a part of the compound ofgeneral formula (5).

The step for obtaining a 20S-allylalcohol intermediate of formula (17)from the compound of formula (16) (step 3) may be performed with asimple metal amide such as lithium diethylamide, but preferably with adialkylaluminium dialkylamide prepared from the corresponding metalamide and dialkylaluminium halide in an inert solvent to give anintended compound at a higher yield in view of the regioselectivity indeprotonation reaction.

Suitable metal amides for use in the above step 3 include lithiumdiethylamide, lithium diisopropylamide, lithium bistrimethylsilylamide,sodium bistrimethylsilylamide, potassium bistrimethylsilylamide,lithium-2,2,6,6-tetramethylpiperidide or the like, preferably lithiumdiisopropylamide, lithium bistrimethylsilylamide, more preferablylithium diisopropylamide. Suitable dialkylaluminium halides includedimethylaluminium chloride, diethylaluminium chloride,diisobutylaluminium chloride, diethylaluminium iodide or the like,preferably dimethylaluminium chloride, diethylaluminium chloride,diisobutylaluminium chloride, more preferably diethylaluminium chloride.

Suitable solvents for use in the above step 3 include hydrocarbon- orhalogen-based solvents or the like, such as hexane, benzene, toluene,dichloromethane, chloroform, preferably benzene and toluene. Thereaction temperature is −40 to 50° C., preferably 0° C. to roomtemperature, more preferably 0° C.

The 20S-allylalcohol intermediate of formula (17) may be oxidized togive a compound of formula (18) (step 4), which is further reduced togive a 20R-allylalcohol intermediate of formula (19) (step 5).

The compounds of formulae (17) and (19) form a part of the compound ofgeneral formula (6), and the compound of formula (18) forms a part ofthe compound of general formula (7).

Oxidization conditions in the oxidization reaction of the above step 4involve using a metal oxidizing agent such as chromium compounds,manganese compounds, osmium compounds, ruthenium compounds; dimethylsulfoxide; carbonyl compounds (Oppenauer oxidization); quinonecompounds, etc. Specific examples include pyridinium chlorochromate,pyridinium dichromate, manganese dioxide, osmium tetraoxide, rutheniumtrichloride, tetrapropylammonium perruthenate, oxalyl chloride/dimethylsulfoxide, triphosgen/dimethyl sulfoxide, sulfur trioxide pyridinecomplex/dimethyl sulfoxide, acetone/aluminium triisopropoxide,cyclohexanone/aluminium triisopropoxide or the like, preferablypyridinium chlorochromate, pyridinium dichromate, manganese dioxide,tetrapropylammonium perruthenate (catalyst) /4-methylmorpholine N-oxide,oxalylchloride/dimethyl sulfoxide, etc.

Reduction conditions in the reduction reaction of the above step 5involve using metal hydrides, metal hydride complex compounds, etc.Specific examples include borane, thexylborane, 9-borabicyclo [3, 3, 1]nonane, catecholborane, diisobutylaluminium hydride, lithiumborohydride, zinc borohydride, sodium borohydride, sodiumtrimethoxyborohydride, sodium cyanoborohydride, sodiumtriacetoxyborohydride, lithium tri-s-butylborohydride, potassiumtri-s-butylborohydride, lithium trisiamylborohydride, potassiumtrisiamylborohydride, lithium triethylborohydride, potassiumtriphenylborohydride, lithium n-butylborohydride, lithium aluminiumhydride, lithium trimethoxyaluminohydride, lithiumtri-t-butoxyaluminohydride, sodium bis(2-methoxyethoxy)aluminohydride orthe like, preferably diisobutylaluminium hydride, sodiumborohydride/cerium chloride, lithium n-butylborohydride, lithiumtriethylborohyhdride, lithium tri-t-butoxyaluminohydride or the like,more preferably sodium borohydride/cerium chloride, lithiumn-butylborohydride, lithium triethylborohydride.

To thus obtained 20S- and 20R-allylalcohol intermediates is introduced aside chain corresponding to the compound of general formula (1) or (4)and the obtained compounds may be subjected to a sequence of reactionsto give a compound of general formula (23) of the present invention asshown by the following scheme:

wherein TBS represents a t-butyldimethylsilyl group, R_(1a) represents asaturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group or a protected hydroxyl group, andR_(1b) represents a saturated or unsaturated aliphatic hydrocarbon groupsubstituted by a hydroxyl group.

A side chain may be introduced into the 20S- or 20R-allylalcohol ofgeneral formula (20) to give a compound of general formula (21) (step6). The side chain can be introduced by reacting a compound of generalformula (13) corresponding to the side chain:

Y—R_(1a)  (13)

wherein R_(1a) and Y have the same meanings as above, with theallylalcohol intermediate mentioned above in the presence of a base.

Suitable bases for use in the above step 6 include alkali metalhydrides, alkali metal alkoxides, metal dialkylamides, alkyl metals orthe like, preferably sodium hydride, potassium hydride, potassiumt-butoxide, lithium diisopropylamide, lithium bistrimethylsilylamide,methyllithium, n-butyllithium, ethylmagnesium bromide or the like, morepreferably sodium hydride, potassium hydride. This reaction may beperformed in the presence of a catalytic amount of a crown ether.Suitable crown ethers include 15-crown-5, 18-crown-6,dibenzo-18-crown-6, preferably 15-crown-5.

Suitable solvents for use in the above step 6 include hydrocarbon-,ether- and amide-based solvents, such as benzene, toluene, diethylether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,N,N-dimethylacetoamide, N,N-dimethylformamide,1,3-dimethyl-2-imidazolidinone,1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone or the like,preferably tetrahydrofuran, 1,2-dimethoxyethane, N,N-dimethylformamide,1,3-dimethyl-2-imidazolidinone, more preferably tetrahydrofuran.

The reaction temperature of the above step 6 is 0° C. to the boilingpoint or decomposition point of the solvent used, preferably roomtemperature to 100° C., more preferably 50 to 80° C.

The side chain may alternatively be introduced by, for example,alkylation with 1-bromo-2,3-epoxy-3-methylbutane as an alkyl halide inthe presence of a base as mentioned above followed by ring-opening ofthe epoxide with a reducing agent such as lithium aluminium hydride,lithium borohydride, lithium tri-s-butylborohydride, lithiumtriethylborohydride. This process may be performed either in two stepsor one step.

Instead of the alkyl halide, epoxides such as isobutyrene oxide,1,2-epoxy-2-ethylbutane, 1,2-epoxy-3-methylbutane,1,2-epoxy-3-ethylpentane may be used to introduce the side chain. Thereaction conditions involve those described in, for example, JPA No.80626/94 (Japanese Patent Application No. 158483/92), preferably usingpotassium t-butoxide as a base in the presence of dibenzo-18-crown-6 intoluene at 100 to 110° C.

The compound of general formula (21), which itself is among compounds ofthe present invention, can be converted into a compound of generalformula (22) by deprotection (step 7). This removal of at-butyldimethylsilyl group is carried out by a conventional procedure.Namely, the reagent used for the reaction includes hydrochloric acid,acidic ion exchange resin, tetrabutylammonium fluoride, hydrogenfluoride/pyridine, hydrogen fluoride/triethylamine, hydrofluoric acid,preferably tetrabutylammonium fluoride. Suitable solvents typicallyinclude etheric solvents, preferably tetrahydrofuran. The reactiontemperature typically ranges from room temperature to 65° C., dependingon the type of the substrate.

The compound of general formula (22) may be further subjected tophotoreaction and thermal isomerization to give a compound of generalformula (23) (step 8).

Steps 6, 7 and 8 may be carried out in the order described above, or inthe order of step 6→step 8→step 7 or the order of step 8→step 6→step 7(i.e. the order is not specifically limited, though step 7 can notprecede step 6).

In the preparation process described above, each intermediate and finalproduct can be purified and isolated by ordinary means such as silicagel column chromatography, thin layer chromatography, recrystallization.

Thus obtained compounds of general formula (1) are useful compounds aspharmaceutical agents such as antitumor agent or antirheumatic agentwith weak hypercalcemic activity, as will be demonstrated in theexamples.

The present invention encompasses compounds of general formula (1)having a steric configuration of either R or S at the 20-position or αor β in the hydroxyl group. The present invention also encompassesgeometrical isomers in cis- and trans-configurations of the compound ofgeneral formula (1) wherein R₁ represents an unsaturated aliphatichydrocarbon group which may be substituted by a hydroxyl group and whichincludes a double bond, as well as possible optical isomers andgeometrical isomers.

More preferred compounds of general formula (1) of the present inventionare those wherein R₁ represents an alkyl group substituted by a hydroxylgroup, particularly 3-hydroxy-3-methylbutyl group. Preferred compoundsare those substituted at the 1-position by a hydroxyl group, thehydroxyl group more preferably having a-configuration. Compounds havingR-configuration at the 20-position are also preferred because of theirstrong differentiation-inducing activity. Compounds wherein X representsa sulfur atom can also be among preferred embodiments.

Specifically, compounds of general formula (1) of the present inventionpreferably include1,3-dihydroxy-20-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene,1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutyl-thio)-9,10-secopregna-5,7,10(19),16-tetraene,1α,3β-dihydroxy-20(R)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.

More preferred specific compounds of general formula (1) of the presentinvention include1α,3β-dihydroxy-20(R)-((E)-4-hydroxy-4-methyl-2-pentenylthio)-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(R)-((E)-4-ethyl-4-hydroxy-2-hexenylthio)-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(S)-(2-hydroxy-2-methylpropyl-thio)-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(R)-(2-hydroxy-2-methylpropylthio)-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutyloxy)-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(S)-(2-ethyl-2-hydroxylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene;1α,3β-dihydroxy-20(R)-(2-ethyl-2-hydroxylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene,etc.

Compounds of general formulae (4) to (7) for preparing these preferredcompounds may also be among more preferred useful compounds as syntheticintermediates.

Compounds of the present invention are preferably formulated and used inappropriate dosage forms such as tablets, granules, parvules, capsules,powders, injections, solutions, suspensions, emulsions, transdermalabsorbents, suppositories in combination with pharmaceuticallyacceptable carriers, excipients, disintegrants, lubricants, binders,perfumes, colorants, etc.

The dosage of compounds of the present invention can be appropriatelychosen depending on the target disease, the condition, body type,constitution, age and sex of the patient, and the administration route,dosage form or other factors, but typically at least in the range of0.001 μg to 0.1 μg, preferably about 0.01 μg daily and at most in therange of 100 μg to 10000 μg, preferably 200 μg to 1000 μg daily, whichmay be divided into 1 to 3 doses.

The following examples further illustrate the present invention, but arenot construed as limiting the same.

EXAMPLES

In the following examples, the infrared absorption spectrum (IR) wasmeasured by HITACHI 270-30. The ¹H NMR was measured by JEOL FX-200 (200MHz) or JEOL EX-270 (270 MHz) using tetramethylsilane as an internalstandard in a CDCl₃ solvent. The mass spectrum (MS) was measured bySHIMADZU GCMS-QP 1000 in EI mode at an ionization voltage of 70 eV. TheUV absorption spectrum (UV) was measured by SHIMADZU UV-240 in ethanol.Column chromatography was run on Merck Kieselgel 60 F254 Art. 9385 andpreparative thin layer chromatography was run on Merck Kieselgel 60 F254Art. 5744 (silica gel thickness 0.5 mm, 20×20 cm) or Art. 5715 (silicagel thickness 0.25 mm, 20×20 cm).

Example 1 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthiopregna-5,7,16-triene

To a solution of1α,3β-bis(tert-butyldimethyl-silyloxy)-16α-hydroxypregna-5,7,17(E)-triene(150 mg, 0.27 mmol) in dichloromethane (5 ml) were added pyridine (0.13ml, 1.61 mmol) and phenyl chlorothionoformate (0.11 ml, 0.81 mmol), andthe mixed solution was stirred at room temperature for one hour and thenconcentrated under reduced pressure. The residue was diluted with hexaneand washed with ice-cooled 1N hydrochloric acid, saturated aqueoussodium bicarbonate solution and brine successively, and the organiclayer was dried over magnesium sulfate. The solvent was removed underreduced pressure, and the resulting residue was purified by preparativethin layer chromatography (0.5 mm×4, hexane:ethyl acetate=9:1, developedonce) to give the title compound as a colorless solid (160 mg, 85%).

IR(KBr): 2920, 2850, 1720, 1490, 1460, 1370, 1245, 1180, 1155, 1095,1000 cm⁻¹. ¹H NMR δ: 0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.89(s,21H), 0.95(s, 3H), 1.60(d, J=7.3 Hz, 3H), 3.72(brs, 1H), 3.94-4.24(m,2H), 5.41(brs, 1H), 5.61(d, J=5.4 Hz, 1H), 5.77(brs, 1H), 7.09-7.44(m,5H). MS m/z: 694(M⁺), 505(100%). UV λ_(max) nm: 205, 270, 282, 293.

Example 2 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5.7,16-triene

In the same manner as in Example 1,1α,3β-bis(tert-butyldimethylsilyloxy)-16α-hydroxypregna-5,7,17(E)-triene(1.50 g, 2.68 mmol), pyridine (1.30 ml, 16.1 mmol) and phenylthionochloroformate (1.11 ml, 8.04 mmol) were reacted in dichloromethane(50 ml) and worked up, then the residue was dissolved in tetrahydrofuran(50 ml) without purification and stirred with Amberlyst 15 (3.00 g) atroom temperature for 36 hours. The resin was filtered and washed withtetrahydrofuran, then the filtrate was concentrated under reducedpressure and the residue was purified by column chromatography(hexane:ethyl acetate=7:1→5:1) to give the title compound as a colorlessoil (1.07 g, 69%).

IR(neat): 3250, 2920, 2850, 1720, 1490, 1460, 1370, 1260, 1190, 1165,1100 cm⁻¹. ¹H NMR δ: 0.08(s, 3H), 0.12(s, 3H), 0.88(s, 9H), 0.95(s, 3H),0.96(s, 3H), 1.60(d, J=6.8 Hz, 3H), 3.76(brs, 1H), 3.99-4.24(m, 2H),5.37-5.46(m, 1H), 5.60-5.68(m, 1H), 5.78(brs, 1H), 7.12-7.45(m, 5H). MSm/z: 580 (M⁺), 277 (100%). UV λ_(max) nm: 205, 270, 282, 293.

Example 3 Preparation of1α-(tert-butyldimethylsilyloxy)-3βhydroxy-20(S)-(3-hydroxy-3-methylbutylthio)pregna-5,7,16-triene

To a solution of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene(81.6 mg, 0.140 mmol) and 4-bromo-2-methyl-2-butanol (117 mg, 0.700mmol) in tetrahydrofuran (1 ml) was added 1M KOH solution in methanol (1ml), and the mixed solution was stirred at room temperature for 30minutes, then concentrated under reduced pressure. The residue wasdiluted with hexane, washed with brine and dried over magnesium sulfate,and then the solvent was distilled off under reduced pressure. Theresulting residue was purified by preparative thin layer chromatography(0.5 mm×2, dichloromethane:ethyl acetate=8:1, developed once) to givethe title compound as a colorless oil (60.3 mg, 79%).

IR(neat): 3400, 2950, 2850, 1460, 1370, 1250, 1200, 1150, 1060 cm⁻¹. ¹HNMR δ: 0.08(s, 3H), 0.13(s, 3H), 0.88(s, 9H), 0.93(s, 3H), 0.94(s, 3H),1.22(s, 6H), 1.43(d, J=6.9 Hz, 3H), 3.51(q, J=6.9 Hz, 1H), 3.75(brs,1H), 3.95-4.17(m, 1H), 5.37-5.45(br, 1H), 5.59-5.69(br, 2H). MS m/z: 546(M⁺), 278 (100%). UV λ_(max) nm: 270, 281, 293.

Example 4 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-methyl-4-triethylsilyloxypentylthio)pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(82.4 mg, 0.142 mmol), 1-bromo-4-methyl-4-triethylsilyloxypentane (209mg, 0.709 mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol(1 ml) were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.5 mm×2, hexane:ethylacetate=3:2, developed once) to give the title compound as a colorlessoil (56.1 mg, 59%).

IR(neat): 3350, 2950, 2850, 1460, 1365, 1255, 1150, 1050 cm⁻¹. ¹H NMR δ:0.08(s, 3H), 0.13(s, 3H), 0.56(q, J=7.7 Hz, 6H), 0.81-1.03(m, 24H),1.19(s, 6H), 1.42(d, J=6.9 Hz, 3H), 3.46(q, J=6.9 Hz, 1H), 3.76(brs,1H), 4.00-4.16(m, 1H), 5.39-5.47(m, 1H), 5.59-5.71(m, 2H). MS m/z:674(M⁺), 277(100%). UV λ_(max) nm: 270, 281, 293.

Example 5 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(5-hydroxy-5-methylhexylthio)pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(82.6 mg, 0.142 mmol), 6-bromo-2-methyl-2-hexanol (139 mg, 0.710 mmol),tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=8:1,developed once) to give 87.2 mg of a product, which was directly used inthe subsequent reaction because it was difficult to separate from6-bromo-2-methyl-2-hexanol.

Example 6 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(2-hydroxy-2-methylpropylthio)pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(83.0 mg, 0.143 mmol), isobutylene oxide (113 mg, 1.56 mmol),tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, hexane:ethyl acetate=1:1, developedonce) to give the title compound as a colorless oil (62.3 mg, 82%).

IR(neat): 3400, 2950, 2850, 1460, 1370, 1250, 1200, 1150, 1060 cm⁻¹. ¹HNMR δ: 0.08(s, 3H), 0.12(s, 3H), 0.88(s, 9H), 0.94(s, 6H), 1.26(s, 3H),1.27(s, 3H), 1.44(d, J=6.9 Hz, 3H), 3.49(q, J=6.9 Hz, 1H), 3.76(brs,1H), 4.00-4.17(m, 1H), 5.36-5.47(m, 1H), 5.59-5.69(m, 2H). MS m/z:532(M⁺), 278(100%). UV λ_(max) nm: 270, 281, 293.

Example 7 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(3-ethyl-3-hydroxypentylthio)pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(82.8 mg, 0.143 mmol), 5-bromo-3-ethyl-3-pentanol (139 mg, 0.715 mmol),tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, dichloromethane:ethyl acetate=8:1,developed once) to give 99.6 mg of a product, which was directly used inthe subsequent reaction because it was difficult to separate from5-bromo-3-ethyl-3-pentanol.

Example 8 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-ethyl-4-hydroxyhexylthio)pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(84.3 mg, 0.145 mmol), 6-bromo-3-ethyl-3-hexanol (152 mg, 0.725 mmol),tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, hexane:ethyl acetate=2:1, developedtwice) to give 76.4 mg of a product, which was directly used in thesubsequent reaction because it was difficult to separate from6-bromo-3-ethyl-3-hexanol.

Example 9 Preparation of1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutylthio)pregna-5,7,16-triene

To a solution of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(3-hydroxy-3-methylbutylthio)pregna-5,7,16-triene(58.5 mg, 0.107 mmol) in tetrahydrofuran (3 ml) was added 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml), andthe mixed solution was heated under reflux for 4 hours. After completionof the reaction, the reaction solution was diluted with ethyl acetate,and washed with ice-cooled 0.5 N hydrochloric acid, saturated aqueoussodium bicarbonate solution and brine successively, and the organiclayer was dried over magnesium sulfate. The solvent was removed underreduced pressure, and the resulting residue was purified by preparativethin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1,developed once) to give the title compound as a pale yellow oil (41.8mg, 90%).

IR (neat): 3400, 2950, 1460, 1370, 1210, 1150, 1060 cm⁻¹. ¹H NMR δ:0.93(s, 3H), 0.96(s, 3H), 1.22(s, 6H), 1.42(d, J=6.8 Hz, 3H), 3.52(q,J=6.8 Hz, 1H ), 3.77(brs, 1H), 3.96-4.16(m, 1H), 5.38-5.48(m, 1H),5.59-5.65(brs, 1H), 5.66-5.76(m, 1H). MS m/z: 432(M⁺), 312(100%). UVλ_(max) nm: 270, 281, 293.

Example 10 Preparation of1α,3β-dihydroxy-20(S)-(4-hydroxy-4-methylpentylthio)pregna-5,7,16-triene

Under the same conditions as in Example 9,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-methyl-4-triethylsilyloxypentylthio)pregna-5,7,16-triene(55.7 mg, 0.0825 mmol), tetrahydrofuran (2 ml) and IMtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1,developed once) to give the title compound as a colorless oil (34.1 mg,92%).

IR(neat): 3400, 2950, 2850, 1460, 1370, 1200, 1150, 1100, 1160 cm⁻¹. ¹HNMR δ: 0.92(s, 3H), 0.97(s, 3H), 1.21(s, 6H), 1.42(d, J=6.9 Hz, 3H),3.47(q, J=6.9 Hz, 1H), 3.77(brs, 1H), 3.98-4.16(m, 1H), 5.39-5.50(m,1H), 5.62(brs, 1H), 5.69-5.77(m, 1H). MS m/z: 446(M⁺), 312(100%). UVλ_(max) nm: 270, 281, 293.

Example 11 Preparation of1α,3β-dihydroxy-20(S)-(5-hydroxy-5-methylhexylthio)pregna-5,7,16-triene

Under the same conditions as in Example 9, the crude1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(5-hydroxy-5-methylhexylthio)pregna-5,7,16-triene(73.2 mg) obtained in Example 5, tetrahydrofuran (2 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1,developed once) to give the title compound as a pale yellow oil (36.1mg, 55%, 2 steps).

IR(neat): 3400, 2950, 1460, 1370, 1200, 1145, 1050 cm⁻¹. ¹H NMR δ:0.93(s, 3H), 0.98(s, 3H), 1.08(s, 6H), 1.42(d, J=6.9 Hz, 3H), 3.46(q,J=6.9 Hz, 1H), 3.78(brs, 1H), 3.98-4.16(m, 1H), 5.41-5.50(m, 1H),5.61(brs, 1H), 5.69-5.78(m, 1H). MS m/z: 460(M⁺), 312(100%). UV λ_(max)nm: 270, 281, 293.

Example 12 Preparation of1α,3β-dihydroxy-20(S)-(2-hydroxy-2-methylpropylthio)pregna-5,7,16-triene

Under the same conditions as in Example 9,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(5-hydroxy-5-methylhexylthio)pregna-5,7,16-triene(60.1 mg, 0.113 mmol), tetrahydrofuran (2 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, dichloromethane:ethanol =7:1,developed once) to give the title compound as a colorless oil (36.3 mg,77%).

IR(neat): 3400, 2950, 1460, 1370, 1250, 1210, 1150, 1060 cm⁻¹. ¹H NMR δ:0.94(s, 3H), 0.97(s, 3H), 1.26(s, 3H), 1.27(s, 3H), 1.43(d, J=6.8 Hz,3H), 3.50(q, J=6.8 Hz, 1H), 3.77(brs, 1H), 3.96-4.16(m, 1H),5.40-5.51(m, 1H), 5.64(brs, 1H), 5.68-5.98(m, 1H). MS m/z: 418(M⁺),312(100%). UV λ_(max) nm: 270, 281, 293.

Example 13 Preparation of1α,3β-dihydroxy-20(S)-(3-ethyl-3-hydroxypentylthio)pregna-5,7,16-triene

Under the same conditions as in Example 9, the crude1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(3-ethyl-3-hydroxypentylthio)pregna-5,7,16-trieneobtained in Example 7, tetrahydrofuran (2 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, dichloromethane:ethanol =7:1,developed once) to give the title compound as a colorless oil (42.0 mg,64%, 2 steps).

IR(neat): 3400, 2950, 1460, 1370, 1150, 1060 cm⁻¹. ¹H NMR δ: 0.85(t,J=7.3 Hz, 6H), 0.94(s, 3H), 0.96(s, 3H), 1.43(d, J=6.8 Hz, 3H), 1.46(q,J=7.3 Hz, 4H), 3.51(q, J=6.8 Hz, 1H), 3.78(brs, 1H), 3.90-4.09(m, 1H),5.38-5.49(m, 1H), 5.63(brs, 1H), 5.66-5.78(m, 1H). MS m/z: 460(M⁺),312(100%). UV λ_(max) nm: 270, 281, 293.

Example 14 Preparation of1α,3β-dihydroxy-20(S)-(4-ethyl-4-hydroxyhexylthio)pregna-5,7,16-triene

Under the same conditions as in Example 9, the crude1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-ethyl-4-hydroxyhexylthio)pregna-5,7,16-triene(71.4 mg) obtained in Example 8, tetrahydrofuran (2 ml) and 1Mtetra-n-butyl-ammonium fluoride solution in tetrahydrofuran (2 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1,developed once) to give the title compound as a colorless oil (45.8 mg,67%, 2 steps).

IR(neat): 3400, 2950, 1450, 1370, 1050 cm⁻¹. ¹H NMR δ: 0.85(t, J=7.3 Hz,6H), 0.94(s, 3H), 0.98(s, 3H), 3.51(q, J=6.8 Hz, 1H), 3.78(brs, 1H),3.98-4.16(m, 1H), 5.38-5.50(m, 1H), 5.63(brs, 1H), 5.69-5.78(m, 1H). MSm/z: 474(M⁺), 312(100%). UV λ_(max) nm: 270, 281, 293.

Example 15 Preparation of1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene

In ethanol (200 ml) was dissolved1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutylthio)pregna-5,7,16-triene(40.2 mg, 0.0929 mmol) and irradiated with a 400 W high pressure mercurylamp through a vicol filter for 3.5 minutes while argon was bubbled withstirring at 0° C., and then the solution was heated under reflux for 1.5hours. After cooling to room temperature, the solvent was removed underreduced pressure and the resulting residue was purified by preparativethin layer chromatography (0.5 mm×1, dichloromethane:ethanol=7:1,developed once, then 0.5 mm×1, hexane:ethyl acetate:ethanol=10:10:1,developed three times) to give the title compound as a colorless oil(3.66 mg, 9.1%).

IR(neat): 3400, 2920, 1440, 1365, 1200, 1140, 1060 cm⁻¹. ¹H NMR δ:0.83(s, 3H), 1.23(s, 6H), 1.42(d, J=7.3 Hz, 3H), 3.49(q, J=7.3 Hz, 1H),4.18-4.32(m, 1H), 4.39-4.52(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.61(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z:432(M⁺), 312(100%). UV λ_(max) nm: 263.

Example 16 Preparation of1α,3β-dihydroxy-20(S)-(4-hydroxy-4-methylpentylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-(4-hydroxy-4-methylpentylthio)pregna-5,7,16-triene(33.4 mg, 0.0748 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 2 minutes andheating under reflux for 2 hours), and then the residue was purified bypreparative thin layer chromatography (0.5 mm×2,dichloromethane:ethanol=7:1, developed once, then 0.5 mm×1, hexane:ethylacetate:ethanol=10:10:1, developed three times) to give the titlecompound as a colorless oil (3.10 mg, 9.3%).

IR(neat): 3400, 2930, 1450, 1370, 1220, 1150, 1060 cm⁻¹. ¹H NMR δ:0.83(s, 3H), 1.21(s, 6H), 1.41(d, J=6.8 Hz, 3H), 3.44(q, J=6.8 Hz, 1H),4.18-4.32(m, 1H), 4.40-4.52(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.59(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z:446(M⁺), 312(100%). UV λ_(max) nm: 263.

Example 17 Preparation of1α,3β-dihydroxy-20(S)-(5-hydroxy-5-methylhexylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-(5-hydroxy-5-methyl-hexylthio)pregna-5,7,16-triene(35.7 mg, 0.0749 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 2.75 minutes andheating under reflux for 2 hours), and then the residue was purified bypreparative thin layer chromatography (0.5 mm×2,dichloromethane:ethanol=8:1, developed once, then 0.5 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed three times) to give the titlecompound as a colorless oil (2.94 mg, 8.2%).

IR(neat): 3400, 2930, 1460, 1370, 1200, 1140, 1050 cm⁻¹. ¹H NMR δ:0.83(s, 3H), 1.21(s, 6H), 1.41(d, J=6.8 Hz, 3H), 3.44(q, J=6.8 Hz, 1H),4.18-4.32(m, 1H), 4.40-4.52(m, 1H), 5.02(brs, 1H), 5.34(brs, 1H),5.59(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z:460(M⁺), 312(100%). UV λ_(max) nm: 263.

Example 18 Preparation of1α,3β-dihydroxy-20(S)-(2-hydroxy-2-methylpropylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-(2-hydroxy-2-methylpropyl-thio)pregna-5,7,16-triene(36.0 mg, 0.0860 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 2.75 minutes andheating under reflux for 2 hours), and then the residue was purified bypreparative thin layer chromatography (0.5 mm×1,dichloromethane:ethanol=7:1, developed once, then 0.5 mm×1, hexane:ethylacetate:ethanol=10:10:1, developed three times) to give the titlecompound as a colorless oil (2.60 mg, 7.2%).

IR(neat): 3400, 2930, 1460, 1370, 1200, 1140, 1060 cm⁻¹. ¹H NMR δ:0.84(s, 3H), 1.25(s, 3H), 1.26(s, 3H), 1.43(d, J=6.9 Hz, 3H), 3.47(q,J=6.9 Hz, 1H), 4.16-4.30(m, 1H), 4.38-4.50(m, 1H), 5.01(brs, 1H),5.34(brs, 1H), 5.62(brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz,1H). MS m/z: 418(M⁺), 312(100%). UV λ_(max) nm: 263.

Example 19 Preparation of1α,3β-dihydroxy-20(S)-(3-ethyl-3-hydroxypentylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-(3-ethyl-3-hydroxypentyl-thio)pregna-5,7,16-triene(41.7 mg, 0.0905 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 2.25 minutes andheating under reflux for 2 hours), and then the residue was purified bypreparative thin layer chromatography (0.5 mm×1,dichloromethane:ethanol=7:1, developed once, then 0.5 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed three times, then 0.5mm×1,dichloromethane:ethyl acetate:ethanol=28:12:1) to give the titlecompound as a colorless oil (3.78 mg, 9.1%).

IR(neat): 3400, 2930, 1450, 1370, 1060 cm⁻¹. ¹H NMR δ: 0.83(s, 3H),0.86(t, J=7.3 Hz, 6H), 1.42(d, J=6.8 Hz, 3H), 1.47(q, J=7.3 Hz, 4H),3.49(q, J=6.8 Hz, 1H), 4.27-4.32(m, 1H), 4.38-4.52(m, 1H), 5.02(brs,1H), 5.34(brs, 1H), 5.61(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d,J=11.2 Hz, 1H). MS m/z: 460(M⁺), 312(100%). UV λ_(max) nm: 263.

Example 20 Preparation of1α,3β-dihydroxy-20(S)-(4-ethyl-4-hydroxyhexylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-(4-ethyl-4-hydroxyhexyl-thio)pregna-5,7,16-triene(44.7 mg, 0.0942 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 2.25 minutes andheating under reflux for 2 hours), and then the residue was purified bypreparative thin layer chromatography (0.5 mm×2, dichloromethane:ethylacetate:ethanol=14:6:1, developed three times, then 0.5 mm×1,hexane:ethyl acetate:ethanol=12:8:1, developed three times) to give thetitle compound as a colorless oil (3.62 mg, 8.1%).

IR(neat): 3400, 2930, 1450, 1370, 1050 cm⁻¹. ¹H NMR δ: 0.83(s, 3H),0.91(t, J=7.3 Hz, 6H), 3.48(q, J=6.8 Hz, 1H), 4.18-4.36(m, 1H),4.38-4.53(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.60(brs, 1H), 6.10(d,J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z: 474(M⁺), 312(100%). UVλ_(max) nm: 263.

Example 21 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-hydroxy-4-methyl-2-pentynylthio)pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(59.4 mg, 0.102 mmol), 5-bromo-2-methyl-3-pentyn-2-ol (90.5 mg, 0.511mmol), tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.5 mm×2, dichloromethane:ethylacetate=5:1, developed twice) to give the title compound as a colorlessoil (41.6 mg, 73%).

IR(neat): 3400, 2950, 2850, 1460, 1370, 1250, 1150, 1060 cm⁻¹. ¹H NMR δ:0.08(s, 3H), 0.12(s, 3H), 0.88(s, 9H), 0.93(s, 3H), 0.94(s, 3H), 1.46(d,J=7.3 Hz, 3H), 1.51(s, 6H), 3.18(d, J=16.6 Hz, 1H), 3.22(d, J=16.6 Hz,1H), 3.67(q, J=7.3 Hz, 1H), 3.76(brs, 1H), 3.96-4.10(m, 1H),5.32-5.44(m, 1H), 5.56-5.71(m, 2H). MS m/z: 556(M⁺), 188(100%). UVλ_(max) nm: 270, 281, 293.

Example 22 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(E)-4-hydroxy-4-methyl-2-pentenylthio}pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(33.5 mg, 0.0577 mmol), (E)-5-bromo-2-methyl-3-penten-2-ol (41.2 mg,0.230 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol(0.5 ml) were reacted and worked up, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate=5:1, developed twice) to give 26.2 mg of aproduct, which was directly used in the subsequent reaction because itwas difficult to separate from (E)-5-bromo-2-methyl-3-penten-2-ol.

Example 23 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-4-methyl-4-triethylsilyloxy-2-pentenylthio}pregna-5,7,16-triene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(91.2 mg, 0.131 mmol), (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene(192 mg, 0.655 mmol), tetrahydrofuran (1.5 ml) and 1M KOH solution inmethanol (1.5 ml) were reacted and worked up, and then the residue waspurified by preparative thin layer chromatography (0.5 mm×2,hexane:dichloromethane:ethyl acetate=160:40:1, developed once) to givethe title compound as a colorless oil (66.3 mg, 64%).

IR(neat): 2950, 2850, 1460, 1170, 1250, 1160, 1080 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.60(q, J=7.3 Hz, 6H), 0.89(s,18H), 0.90-1.04(m, 15H), 1.37(s, 6H), 1.44(d, J=6.8 Hz, 3H), 3.33(dd,J=13.0, 6.8 Hz, 1H), 3.41-3.60(m, 2H), 3.72(brs, 1H), 3.96-4.16(m, 1H),5.23-5.52(m, 3H), 5.55-5.68(m, 2H). MS m/z: 786(M⁺), 278(100%). UVλ_(max) nm: 270, 281, 293.

Example 24 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-ethyl-4-hydroxy-2-hexynylthio)pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene (60.8 mg, 0.105 mmol),6-bromo-3-ethyl-4-hexyn-3-ol (108 mg, 0.525 mmol), tetrahydrofuran (1ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up,and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, dichioromethane ethyl acetate=5:1, developedtwice) to give the title compound as a colorless oil (38.4 mg, 63%).

IR(neat): 3400, 2950, 2850, 1460, 1370, 1250, 1150, 1060 cm⁻¹. ¹H NMR δ:0.08(s, 3H), 0.12(s, 3H), 0.88(s, 9H), 0.92(s, 3H), 0.94(s, 3H), 1.03(t,J=7.3 Hz, 6H), 1.46(d, J=6.8 Hz, 3H), 1.66(q, J=7.3 Hz, 4H), 3.20(d,J=16.6 Hz, 1H), 3.24(d, J=16.6 Hz, 1H), 3.68(q, J=6.8 Hz, 1H), 3.75(brs,1H), 3.96-4.12(m, 1H), 5.35-5.44(m, 1H), 5.57-5.71 (m, 2H). MS m/z: 566(M⁺-H₂O), 187 (100%). UV λ_(max) nm: 270, 281, 293.

Example 25 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(E)-4-ethyl-4-hydroxy-2-hexenylthio}pregna-5.7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonyl-thiopregna-5,7,16-triene(33.1 mg, 0.0570 mmol), (E)-6-bromo-3-ethyl-4-hexen-3-ol (47.4 mg, 0.229mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.5 mm×1, dichloromethane:ethylacetate=5:1, developed twice) to give the title compound as a colorlessoil (28.2 mg, 84%).

IR(neat): 3400, 2920, 2850, 1460, 1370, 1250, 1150, 1060 cm⁻¹. ¹H NMR δ:0.08(s, 3H), 0.12(s, 3H), 0.87(t, J=7.3 Hz, 6H), 0.88(s, 9H), 1.42(d,J=6.8 Hz, 3H), 1.54(q, J=7.3 Hz, 4H), 3.10(dd, J=12.6, 5.5Hz, 1H),3.12(dd, J=12.6, 5.5Hz, 1H), 3.45(q, J=6.8 Hz, 1H), 3.75(brs, 1H),3.96-4.15(m, 1H), 5.35-5.44(m, 1H), 5.45-5.73(m, 4H). MS m/z: 586(M⁺),277(100%). UV λ_(max) nm: 270, 281, 293.

Example 26 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(Z)-4-ethyl-4-triethylsilyloxy-2-hexenylthio}pregna-5,7,16-triene

Under the same conditions as in Example 3,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthio-pregna-5,7,16-triene(33.0 mg, 0.0568 mmol), (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene(91.0 mg, 0.284 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution inmethanol (0.5 ml) were reacted and worked up, and then the residue waspurified by preparative thin layer chromatography (0.5 mm×1,hexane:ethyl acetate=2:1, developed once) to give the title compound asa pale yellow oil (23.8 mg, 60%).

IR(neat): 3400, 2950, 2850, 1460, 1350, 1250, 1140, 1060 cm⁻¹. ¹H NMR δ:0.08(s, 3H), 0.12(s, 3H), 0.62(q, J=7.5 Hz, 6H), 0.80-1.05(m, 30H),1.44(d, J=6.8 Hz, 3H), 1.57(q, J=7.3 Hz, 4H), 3.28-3.59(m, 3H),3.76(brs, 1H), 3.97-4.28(m, 1H), 5.23(d, J=11.2 Hz, 1H), 5.35-5.53(m,2H), 5.56-5.72(m, 2H). MS m/z: 700(M⁺), 278(100%). UV λ_(max) nm: 270,281, 293.

Example 27 Preparation of1α-(tert-butyldimethylsilyloxy)-3o-hydroxy-20(S)-(4-hydroxy-4-methyl-2-pentynylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α(-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-hydroxy-4-methyl-2-pentynylthio)pregna-5,7,16-triene(41.6 mg, 0.0747 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 2 minutes andheating under reflux for 1.5 hours), and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, dichloromethaneethyl acetate=6:1, developed three times, then 0.5 mm×1, hexane:ethylacetate=3:1, developed three times) to give the title compound as acolorless oil (3.8 mg, 9.1%).

IR(neat): 3400, 2930, 2850, 1460, 1360, 1245, 1160, 1060 cm⁻¹. ¹H NMR δ:0.09(s, 6H), 0.82(s, 3H), 0.90(s, 9H), 1.45(d, J=7.3Hz, 3H), 1.51(s,6H), 3.18(d, J=16.6 Hz, 1H), 3.21(d, J=16.6 Hz, 1H), 3.66(q, J=7.3Hz,1H), 4.16-4.28(m, 1H), 4.34-4.43(m, 1H), 4.92(brs, 1H), 5.27(brs, 1H),5.64(brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.32(d, J=11.2 Hz, 1H). MS m/z:556(M⁺), 248(100%). UV λ_(max) nm: 264.

Example 28 Preparation of1α-(tert-butyldimethylsilyloxy)-3βhydroxy-20(S)-{(E)-4-hydroxy-4-methyl-2-pentenylthio}-9,10-secopregna-5,7.10(19),16-tetraene

Using the crude1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(E)-4-hydroxy-4-methyl-2-pentenylthio}pregna-5,7,16-triene(25.8 mg) obtained in Example 22 and ethanol (200 ml), the reaction wasperformed by the same procedure as in Example 15 (irradiation for 2minutes and heating under reflux for 2 hours), and then the residue waspurified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate=6:1, developed four times) to give a crudepurification product (3.1 mg) and recovered raw materials (10.5 mg). Therecovered raw materials (10.5 mg) were irradiated for 2 minutes andheated under reflux for 2 hours again, and the residue was purified bypreparative thin layer chromatography (0.5 mm×1, dichloromethane:ethylacetate=6:1, developed four times) to give a crude purification product(1.8 g), which was combined with the previously obtained one andpurified by preparative thin layer chromatography (0.5 mm×1,hexane:ethyl acetate=4:1, developed four times) to give the titlecompound as a colorless oil (2.0 mg, 6.2%, 2 steps).

IR(neat): 3400, 2930, 1460, 1370, 1250, 1060 cm⁻¹. ¹H NMR δ: 0.09(s,6H), 0.82(s, 3H), 0.90(s, 9H), 1.32(s, 6H), 1,41(d, J=6.8Hz, 3H),2.99-3.19(m, 2H), 3.41(q, J=6.8Hz, 1H), 4.16-4.28(m, 1H), 4.32-4.43(m,1H), 4.93(brs, lH), 5.27(brs, 1H), 5.58(brs, 1H), 5.10-5.78(m, 2H),6.10(d, J=11.2 Hz, 1H), 6.33 (d, J=11.2 Hz, 1H). MS m/z: 558(M⁺),160(100%). UV λ_(max) nm: 263.

Example 29 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(z)-4-methyl-4-triethylsilyloxy-2-pentenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-4-methyl-4-triethylsilyloxy-2-pentenylthio}pregna-5,7,16-triene(66.1 mg, 0.0839 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 3 minutes andheating under reflux for 2 hours), and then the residue was purified bypreparative thin layer chromatography (0.5 mm×3,hexane:dichloromethane=4:1, developed twice) to give 20.9 mg of acompound, which was directly used in the subsequent reaction because itwas difficult to separate from raw materials.

Example 30 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-ethyl-4-hydroxy-2-hexynylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-ethyl-4-hydroxy-2-hexynylthio)pregna-5,7,16-triene(21.9 mg, 0.0374 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 3.45 minutes andheating under reflux for 1.5 hours), and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, dichloromethaneethyl acetate=6:1, developed twice, then 0.5 mm×1, hexane:ethylacetate=3:1, developed four times) to give the title compound as acolorless oil (1.8 mg, 8.2%).

IR(neat): 3400, 2930, 2850, 1460, 1370, 1250, 1060 cm⁻¹. ¹H NMR δ:0.09(s, 3H), 0.81(s, 3H), 0.89(s, 9H), 1.03(t, J=7.3Hz, 6H), 1.45(d,J=6.8Hz, 3H), 1.67(q, J=7.3Hz, 4H), 3.20(d, J=16.8Hz, 1H), 3.23(d,J=16.8Hz, 1H), 3.67(q, J=6.8Hz, 1H), 4.14-4.28(m, 1H), 4.32-4.43(m, 1H),4.93(brs, 1H), 5.27(brs, 1H), 5.63(brs, 1H), 6.10(d, J=11.2Hz, 1H),6.32(d, J=11.2Hz, 1H). MS m/z: 584(M⁺), 248(100%). UV λ_(max) nm: 264.

Example 31 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(E)-4-ethyl-4-hydroxy-2-hexenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(E)-4-ethyl-4-hydroxy-2-hexenylthio}pregna-5,7,16-triene(26.3 mg, 0.0448 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 3 minutes andheating under reflux for 1.5 hours), and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate=6:1, developed three times, then 0.5 mm×1,hexane:ethyl acetate=3:1, developed three times) to give the titlecompound as a colorless oil (2.1 mg, 8.0%).

IR(neat): 3400, 2930, 2850, 1460, 1375, 1255, 1060 cm⁻¹. ¹H NMR δ:0.09(s, 6H), 0.82(s, 3H), 0.84-0.98(m, 15H), 1.41(d, J=6.8 Hz, 3H),1.54(q, J=7.3 Hz, 4H), 3.07-3.18(m, 2H), 3.42(q, J=6.8 Hz, 1H),4.15-4.29(m, 1H), 4.33-4.44(m, 1H), 4.93(brs, 1H), 5.27(brs, 1H),5.44-5.76(m, 3H), 6.10(d, J=11.2 Hz, 1H), 6.32(d, J=11.2 Hz, 1H). MSm/z: 586(M⁺), 426(100%). UV λ_(max) nm: 263.

Example 32 Preparation of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(Z)-4-ethyl-4-triethylsilyloxy-2-hexenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(Z)-4-ethyl-4-triethylsilyloxy-2-hexenylthio}pregna-5,7,16-triene(23.7 mg, 0.0338 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 3.5 minutes andheating under reflux for 1.5 hours), and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate=6:1, developed three times) to give thetitle compound as a colorless oil (1.3 mg, 5.5%).

IR(neat): 3400, 2925, 2850, 1460, 1370, 1250, 1050 cm⁻¹. ¹H NMR δ:0.09(s, 6H), 0.62(q, J=7.5 Hz, 6H), 0.76-1.05(m, 27H), 1.43(d, J=6.8 Hz,3H), 1.56(q, J=7.5 Hz, 4H), 3.28-3.60(m, 3H), 4.16-4.29(m, 1H),4.32-4.43(m, 1H), 4.93(brs, 1H), 5.18-5.30(m, 2H), 5.32-5.55(m, 1H),5.59(brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.32(d, J=11.2 Hz, 1H). MS m/z:700(M⁺), 202(100%). UV λ_(max) nm: 263.

Example 33 Preparation of1α,3β-dihydroxy-20(S)-(4-hydroxy-4-methyl-2-pentynylthio}-9,10-secopregna-5,7,10(19),16-tetraene

To a solution of1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-hydroxy-4-methyl-2-pentynylthio)-9,10-secopregna-5,7,10(19),16-tetraene(3.4 mg, 0.00611 mmol) in tetrahydrofuran (2 ml) was added 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (1 ml), andthe mixed solution was reacted at room temperature for 13 hours. Thereaction solution was diluted with ethyl acetate and washed withice-cooled 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonatesolution and brine successively, and the organic layer was dried overmagnesium sulfate, then the solvent was removed under reduced pressure.The resulting residue was purified by preparative thin layerchromatography (0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1,developed three times) to give the title compound as a colorless oil(0.653 mg, 24%).

IR(neat): 3400, 2930, 1450, 1370, 1250, 1160, 1050 cm⁻¹. ¹H NMR δ:0.84(s, 3H), 1.45(d, J=7.3 Hz, 3H), 1.51(s, 6H), 3.17(d, J=16.6 Hz, 1H),3.20(d, J=16.6 Hz, 1H), 3.66(q, J=7.3 Hz, 1H), 4.28-4.31(m, 1H),4.38-4.49(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.65(brs, 1H), 6.10(d,J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z: 442(M⁺), 311(100%). UVλ_(max) nm: 263.

Example 34 Preparation of1α,3β-dihydroxy-20(S)-{(E)-4-hydroxy-4-methyl-2-pentenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

By the same procedure as in Example 33,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(E)-4-hydroxy-4-methyl-2-pentenylthio}-9,10-secopregna-5,7,10(19),16-tetraene(2.0 mg, 0.00358 mmol), tetrahydrofuran (1 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.5 ml) werereacted (3 days) and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed three times) to give the titlecompound as a colorless oil (0.744 mg, 47%).

IR(neat): 3400, 2920, 1460, 1370, 1060 cm⁻¹. ¹H NMR δ: 0.88(s, 3H),1.32(s, 6H), 1.41(d, J=6.8 Hz, 3H), 2.96-3.20(m, 2H), 3.40(d, J=6.8 Hz,1H), 4.17-4.32(m, 1H), 4.39-4.49(m, 1H), 5.02(brs, 1H), 5.34(brs, 1H),5.60-5.77(m, 2H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MSm/z: 426(M⁺-H₂O), 105(100%). UV λ_(max) nm: 264.

Example 35 Preparation of1α,3β-dihydroxy-20(S)-{(Z)-4-hydroxy-4-methyl-2-pentenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

By the same procedure as in Example 33, the crude1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-4-methyl-4-triethylsilyloxy-2-pentenylthio}-9,10-secopregna-5,7,10(19),16-tetraene(20.9 mg) obtained in Example 29, tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (40 hours) and worked up, and then the residue was purified bypreparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed five times) to give the title compoundas a colorless oil (1.67 mg, 14%, 2 steps).

IR(neat): 3400, 2930, 1450, 1370, 1210, 1150, 1060 cm⁻¹. ¹H NMR δ:0.84(s, 3H), 1.36(s, 6H), 1.44(d, J=7.3 Hz, 3H), 3.34(dd, J=12.2, 6.8Hz,1H), 3.62-3.77(m, 2H), 4.17-4.32(m, 1H), 4.38-4.50(m, 1H), 5.01(brs,1H), 5.34(brs, 1H), 5.35-5.58(m, 2H), 5.60(brs, 1H), 6.10(d, J=11.2 Hz,1H), 6.37(d, J=11.2 Hz, 1H). MS m/z: 444(M⁺), 312(100%). UV λ_(max) nm:264.

Example 36 Preparation of1α,3β-dihydroxy-20(S)-(4-ethyl-4-hydroxy-2-hexynylthio)-9,10-secopregna-5,7,10(19),16-tetraene

By the same procedure as in Example 33,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-ethyl-4-hydroxy-2-hexynylthio)-9,10-secopregna-5,7,10(19),16-tetraene(1.8 mg, 0.00308 mmol), tetrahydrofuran (2 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (40 hours) and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed three times) to give the titlecompound as a colorless oil (0.699 mg, 48%).

IR(neat): 3400, 2930, 1450, 1370, 1230, 1150, 1060 cm⁻¹. ¹H NMR δ:0.82(s, 3H), 1.02(t, J=7.3 Hz, 6H), 1.44(d, J=6.8 Hz, 3H), 1.65(q, J=7.3Hz, 4H), 3.28(d, J=16.7 Hz, 1H), 3.32(d, J=16.7 Hz, 1H), 3.66(q, J=6.8Hz, 1H), 4.16-4.31(m, 1H), 4.36-3.52(m, 1H), 4.99(brs, 1H), 5.32(brs,1H), 5.61(brs, 1H), 6.07(d, J=11.2 Hz, 1H), 6.35(d, J=11.2 Hz, 1H). MSm/z: 452(M⁺-H₂O), 91(100%). UV λ_(max) nm: 264.

Example 37 Preparation of1α,3β-dihydroxy-20(S)-{(E)-4-ethyl-4-hydroxy-2-hexenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

By the same procedure as in Example 33,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(E)-4-ethyl-4-hydroxy-2-hexenylthio}-9,10-secopregna-5,7,10(19),16tetraene(1.9 mg, 0.00324 mmol), tetrahydrofuran (2 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (40 hours) and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethyl acetateethanol=12:8:1, developed three times) to give the title compound as acolorless oil (0.748 mg, 49%).

IR(neat): 3400, 2920, 1450, 1370, 1270, 1050 cm⁻¹. ¹H NMR δ: 0.86(t,J=7.3 Hz, 6H), 0.88(s, 3H), 1.41(d, J=6.8 Hz, 3H), 1.53(q, J=7.3 Hz,4H), 3.07-3.17(m, 2H), 3.42(q, J=6.8 Hz, 1H), 4.17-4.29(m, 1H),4.38-4.50(m, 1H), 5.02(brs, 1H), 5.34(brs, 1H), 5.43-5.80(m, 3H),6.10(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z: 454(M⁺-H₂O),161(100%). UV λ_(max) nm: 264.

Example 38 Preparation of1α,3β-dihydroxy-20(S)-{(Z)-4-ethyl-4-hydroxy-2-hexenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

By the same procedure as in Example 33,1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-{(Z)-4-ethyl-4-triethylsilyloxy-2-hexenylthio}-9,10-secopregna-5,7,10(19),16-tetraene(1.2 mg, 0.00171 mmol), tetrahydrofuran (2 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (40 hours) and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed twice) to give the title compound as acolorless oil (0.357 mg, 44%).

IR(neat): 3400, 2920, 1450, 1370, 1060 cm⁻¹. ¹H NMR δ: 0.84(s, 3H),0.91(t, J=7.5 Hz, 6H), 1.44(d, J=6.8 Hz, 3H), 1.57(q, J=7.5 Hz, 4H),3.27-3.58(m, 3H), 4.17-4.31(m, 1H), 4.40-4.52(m, 1H), 5.01(brs, 1H),5.23-5.37(m, 2H), 5.44-5.70(m, 2H), 6.10(d, J=11.2 Hz, 1H), 6.37(d,J=11.2 Hz, 1H). MS m/z: 454(M⁺-H₂O), 312(100%). UV λ_(max) nm: 263.

Example 39 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-16α-hydroxy-9,10-secopregna-5,7,10(19)17(E)-tetraene

Using1α,3β-bis(tert-butyldimethylsilyloxy)-16α-hydroxypregna-5,7,17(E)-triene(103 mg, 0.184 mmol) and ethanol (200 ml), the reaction was performed bythe same procedure as in Example 15 (irradiation for 5 minutes andheating under reflux for 2 hours), and then the residue was purified bypreparative thin layer chromatography (0.5 mm×3, hexane:ethylacetate=9:1, developed four times, then 0.5 mm×2, hexane:ethylacetate=9:1, developed four times) to give the title compound as acolorless oil (24.1 mg, 23%).

IR(neat): 3350, 2930, 2855, 1460, 1380, 1255, 1080 cm⁻¹. ¹H NMR δ:0.06(s, 12H), 0.74(s, 3H), 0.88(s, 18H), 1.74(d, J=7.3 Hz, 3H),4.12-4.28(m, 1H), 4.32-4.52(m, 2H), 4.86(d, J=2.0 Hz, 1H), 5.19(d, J=2.0Hz, 1H), 5.64(q, J=7.3 Hz, 1H), 6.00(d, J=11.2 Hz, 1H), 6.23(d, J=11.2Hz, 1H). MS m/z: 558(M⁺), 248(100%). UV λ_(max) nm: 262.

Example 40 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 1,1α,3βbis(tert-butyldimethylsilyloxy)-16(-hydroxy-9,10-secopregna-5,7,10(19),17(E)-tetraene(24.0 mg, 0.0430 mmol), dichloromethane (2.5 ml), pyridine (0.0209 ml,0.258 mmol) and phenyl chlorothionoformate (0.0178 ml, 0.129 mmol) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×1, hexane:ethyl acetate=9:1, developedonce) to give the title compound as a colorless oil (17.9 mg, 60%).

IR(neat): 2925, 2850, 1730, 1490, 1470, 1255, 1190, 1160, 1100 cm⁻¹. ¹HNMR δ: 0.07(s, 12H), 0.85(s, 3H), 0.88(s, 18H), 1.59(d, J=6.8 Hz, 3H),4.04-4.28(m, 2H), 4.39(t, J=4.9 Hz, 1H), 4.88(d, J=2.0 Hz, 1H), 5.19(d,J=2.0 Hz, 1H), 5.74(brs, 1H), 6.09(d, J=11.2 Hz, 1H), 6.24(d, J=11.2 Hz,1H), 7.12-7.44(m, 5H). MS m/z: 694(M⁺), 248(100%). UV λ_(max) nm: 210,263.

Example 41 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(2.0 mg, 0.00288 mmol), 4-bromo-2-methyl-2-butanol (2.4 mg, 0.0144mmol), tetrahydrofuran (0.25 ml) and 1M KOH solution in methanol (0.25ml) were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate=3:1, developed once) to give the title compound as a colorlessoil (1.5 mg, 79%).

IR(neat): 3400, 2920, 2850, 1460, 1360, 1250, 1080 cm⁻¹. ¹H NMR δ:0.07(s, 12H), 0.81(s, 3H), 0.87(s, 9H), 0.88(s, 9H), 1.23(s, 6H),1.42(d, J=6.8 Hz, 3H), 3.49(q, J=6.8 Hz, 1H), 4.11-4.24(m, 1H),4.26-4.31(m, 1H), 4.84(brs, 1H), 5.19(brs, 1H), 5.60(brs, 1H), 6.10(d,J=11.2 Hz, 1H), 6.24(d, J=11.2 Hz, 1H). MS m/z: 660(M⁺), 248(100%). UVλ_(max) nm: 263.

Example 42 Preparation of1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene(1.5 mg, 0.00227 mmol), tetrahydrofuran (1 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.5 ml) werereacted (1.5 hours) and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed three times) to give the titlecompound as a colorless oil (0.511 mg, 52%). Each spectrum of thecompound obtained here was consistent with that of the compound obtainedin Example 15.

Example 43 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-16-oxopregna-5,7,17(E)-triene

To a solution of1α,3β-bis(tert-butyldimethyl-silyloxy)-16α-hydroxypregna-5,7,17(E)-triene(2.01 g, 3.60 mmol) in chloroform (150 ml) was added manganese dioxide(40 g), and the mixed solution was reacted for 2 hours underultrasonication. The reaction solution was filtered and the filtrate wasconcentrated, and then the residue was purified by column chromatography(hexane:dichloromethane:ethyl acetate=18:2:1) to give the title compoundas a colorless solid (1.45 g, 73%).

IR(KBr): 2950, 2850, 1730, 1650, 1460, 1380, 1255, 1100 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 3H), 0.08(s, 3H), 0.12(s, 3H), 0.89(s, 18H),0.97(s, 3H), 0.99(s, 3H), 1.88(d, J=7.3 Hz, 3H), 3.73(brs, 1H),3.96-4.16(m, 1H), 5.30-5.39(m, 1H), 5.56-5.65(m, 1H), 6.56(q, J=7.3 Hz,1H). MS m/z: 556(M⁺), 367(100%). UV λ_(max) nm: 242, 258, 270, 281, 293.

Example 44 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-16β-hydroxypregna-5,7,17(E)-triene

To a solution of1α,3β-bis(tert-butyldimethyl-silyloxy)-16-oxopregna-5,7,17(E)-triene(1.45 g, 2.60 mmol) and cerium (III) chloride heptahydrate (1.45 g, 3.90mmol) in methanol (20 ml) and tetrahydrofuran (80 ml) cooled at 0° C.was added sodium borohydride (490 mg, 13.0 mmol) by portions. Thereaction solution was stirred at room temperature for one hour, thenconcentrated under reduced pressure, and the residue was taken intowater and extracted with ethyl acetate. The organic layer was washedwith brine and then dried over magnesium sulfate, and the solvent wasdistilled off under reduced pressure. The resulting residue was purifiedby column chromatography (hexane:ethyl acetate=10:1) to give the titlecompound as a colorless solid (1.29 g, 89%) and1α,3β-bis(tert-butyldimethyl-silyloxy)-16α-hydroxypregna-5,7,17(E)-triene(85 mg, 5.8%).

Title compound: IR(KBr): 3300, 2950, 2850, 1460, 1370, 1245, 1100, 1000cm⁻¹. ¹H NMR δ: 0.05(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.88(s, 18H),0.93(s, 3H), 1.00(s, 3H), 1.76(dd, J=7.3, 2.0 Hz, 3H), 3.71(brs, 1H),3.93-4.16(m, 1H), 4.49(t, J=7.8 Hz, 1H), 5.33-5.42(m, 1H), 5.47-5.64(m,2H). MS m/z: 558(M⁺), 369(100%). UV λ_(max) nm: 270, 281, 293.

Example 45 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-16β-hydroxy-9,10-secopregna-5,7,10(19)17(E)-tetraene

Using1α,3β-bis(tert-butyldimethylsilyloxy)-16β-hydroxypregna-5,7,17(E)-triene(115 mg, 0.205 mmol) and ethanol (200 ml), the reaction was performed bythe same procedure as in Example 15 (irradiation for 5.5 minutes andheating under reflux for 2 hours), and then the residue was purified bypreparative thin layer chromatography (0.5 mm×3, hexane:ethylacetate=8:1, developed three times) to give the title compound as acolorless oil (27.0 mg, 23%).

IR(neat): 3400, 2950, 2850, 1470, 1370, 1250, 1075 cm⁻¹. ¹H NMR δ:0.06(s, 6H), 0.07(s, 6H), 0.88(s, 18H), 0.91(s, 3H), 1.74(dd, J=6.8, 1.5Hz, 3H), 4.13-4.29(m, 1H), 4.32-4.55(m, 2H), 4.87(d, J=1.9 Hz, 1H),5.20(d, J=1.9 Hz, 1H), 5.57(dq, J=6.8, 1.5 Hz, 1H), 6.04(d, J=11.2 Hz,1H), 6.21(d, J=11.2 Hz, 1H). MS m/z: 558(M⁺), 427(100%). UV λ_(max) nm:263.

Example 46 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7.10(19),16-tetraene

Under the same conditions as in Example 1,1α,3β-bis(tert-butyldimethylsilyloxy)-16β-hydroxy-9,10-secopregna-5,7,10(19),17(E)-tetraene(53.1 mg, 0.0950 mmol), dichloromethane (5 ml), pyridine (0.0461 ml,0.570 mmol) and phenyl chlorothionoformate (0.0394 ml, 0.285 mmol) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.5 mm×2, hexane:ethyl acetate=8:1, developedonce) to give the title compound as a colorless oil (55.4 mg, 84%).

IR(neat): 2930, 2850, 1730, 1490, 1470, 1370, 1255, 1190, 1160, 1100,1010 cm⁻¹. ¹H NMR δ: 0.06(s, 12H), 0.73(s, 3H), 0.87(s, 9H), 0.88(s,9H), 1.61(d, J=6.8 Hz, 3H), 4.08(q, J=6.8 Hz, 1H), 4.12-4.28(m, 1H),4.32-4.44(m, 1H), 4.88(d, J=1.9 Hz, 1H), 5.19(d, J=1.9 Hz, 1H),5.72(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.24(d, J=11.2 Hz, 1H),7.07-7.48(m, 5H). MS m/z: 694 (M⁺), 248 (100%). UV λ_(max) nm: 215, 263.

Example 47 Preparation of1α,3β-dihydroxy-20(R)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(3.3 mg, 0.00475 mmol), 4-bromo-2-methyl-2-butanol (4.0 mg, 0.0238mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate=3:1, developed once) to give 3.6 mg of a product, to which wereadded tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoridesolution in tetrahydrofuran (0.3 ml). By the same procedure as inExample 9, the mixed solution was reacted (1.5 hours) and worked up, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (1.15 mg, 56%).

IR(neat): 3400, 2920, 1450, 1370, 1200, 1060 cm⁻¹. ¹H NMR δ: 0.74(s,3H), 1.24(s, 6H), 1.47(d, J=6.8 Hz, 3H), 3.40(q, J=6.8 Hz, 1H),4.14-4.29(m, 1H), 4.34-4.48(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.29(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z:432(M⁺), 312(100%). UV λ_(max) nm: 263.

Example 48 Preparation of1α,3β-dihydroxy-20(R)-(4-hydroxy-4-methylpentylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(3.9 mg, 0.00561 mmol), 1-bromo-4-methyl-4-triethylsilyloxypentane (8.3mg, 0.0281 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution inmethanol (0.5 ml) were reacted and worked up, and then the residue waspurified by preparative thin layer chromatography (0.25 mm×1,hexane:dichloromethane: ethyl acetate=160:40:1, developed once) to give3.1 mg of a product, to which were added tetrahydrofuran (1 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.5 ml). Bythe same procedure as in Example 9, the mixed solution was reacted (1.5hours) and worked up, and then the residue was purified by preparativethin layer chromatography (0.25 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed twice) to give the title compound as acolorless oil (0.614 mg, 24%).

IR(neat): 3400, 2920, 1450, 1370, 1270, 1200, 1050 cm⁻¹. ¹H NMR δ:0.74(s, 3H), 1.22(s, 6H), 1.45(d, J=6.9 Hz, 3H), 3.36(q, J=6.9 Hz, 1H),4.18-4.30(m, 1H), 4.39-4.50(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.57(brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z:428(M⁺-H₂O), 312(100%). UV λ_(max) nm: 264.

Example 49 Preparation of1α,3β-dihydroxy-20(R)-(5-hydroxy-5-methylhexylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(3.8 mg, 0.00547 mmol), 6-bromo-2-methyl-2-hexanol (5.3 mg, 0.0274mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate=3:1, developed once) to give 3.1 mg of a product, to which wereadded tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoridesolution in tetrahydrofuran (0.3 ml). By the same procedure as inExample 9, the mixed solution was reacted (1.5 hours) and worked up, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (1.34 mg, 60%).

IR(neat): 3400, 2920, 1450, 1370, 1200, 1060 cm⁻¹. ¹H NMR δ: 0.73(s,3H), 1.21(s, 6H), 1.45(d, J=6.8 Hz, 3H), 3.34(q, J=6.8 Hz, 1H),4.28-4.32(m, 1H), 4.38-4.51(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.56(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z:442(M⁺-H₂O), 312(100%). UV λ_(max) nm: 264.

Example 50 Preparation of1α,3β-dihydroxy-20(R)-(2-hydroxy-2-methylpropylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(3.9 mg, 0.00561 mmol), isobutylene oxide (2.0 mg, 0.0281 mmol),tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.25 mm×1, hexane:ethyl acetate=3:1,developed once) to give 2.2 mg of a product, to which were addedtetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoride solution intetrahydrofuran (0.3 ml). By the same procedure as in Example 9, themixed solution was reacted (1.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.25mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times) togive the title compound as a colorless oil (0.929 mg, 40%).

IR(neat): 3400, 2920, 1450, 1370, 1200, 1145, 1055 cm⁻¹. ¹H NMR δ:0.73(s, 3H), 1.26(s, 3H), 1.27(s, 3H), 1.46(d, J=6.9 Hz, 3H), 3.39(q,J=6.9 Hz, 1H), 4.18-4.29(m, 1H), 4.41-4.50(m, 1H), 5.01(brs, 1H),5.34(brs, 1H), 5.60(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz,1H). MS m/z: 418(M⁺), 91(100%). UV λ_(max) nm: 264.

Example 51 Preparation of1α,3β-dihydroxy-20(R)-(3-ethyl-3-hydroxypentylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(4.0 mg, 0.00575 mmol), 5-bromo-3-ethyl-3-pentanol (5.6 mg, 0.0288mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate=3:1, developed once) to give 3.0 mg of a product, to which wereadded tetrahydrofuran (1 ml) and 1M tetra-n-butylammonium fluoridesolution in tetrahydrofuran (0.3 ml). By the same procedure as inExample 9, the mixed solution was reacted (1.5 hours) and worked up, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (1.48 mg, 56%).

IR(neat): 3400, 2920, 1465, 1370, 1200, 1060 cm⁻¹. ¹H NMR δ: 0.74(s,3H), 0.86(t, J=7.4 Hz, 6H), 1.40-1.53(m, 7H), 3.39(q, J=6.9 Hz, 1H),4.18-4.30(m, 1H), 4.38-4.51(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.58(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z:460(M⁺), 312(100%). UV λ_(max) nm: 264.

Example 52 Preparation of1α,3β-dihydroxy-20(R)-(4-ethyl-4-hydroxyhexylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(5.0 mg, 0.00719 mmol), 6-bromo-3-ethyl-3-hexanol (7.5 mg, 0.0360 mmol),tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) werereacted and worked up, and then the residue was purified by preparativethin layer chromatography (0.25 mm×1, hexane:ethyl acetate=3:1,developed once) to give 4.2 mg of a product, to which were addedtetrahydrofuran (0.5 ml) and 1M tetra-n-butylammonium fluoride solutionin tetrahydrofuran (0.3 ml). By the same procedure as in Example 9, themixed solution was reacted (1.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.25mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times) togive the title compound as a colorless oil (1.14 mg, 33%).

IR(neat): 3400, 2920, 1455, 1370, 1250, 1140, 1050 cm⁻¹. ¹H NMR δ:0.74(s, 3H), 0.92(t, J=6.9 Hz, 6H), 3.39(q, J=6.8 Hz, 1H), 4.18-4.32(m,1H), 4.39-4.52(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.58(brs, 1H),6.11(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z: 456(M⁺-H₂O),312(100%). UV λ_(max) nm: 264.

Example 53 Preparation of1α,3β-dihydroxy-20(R)-(4-hydroxy-4-methyl-2-pentynylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(4.3 mg, 0.00619 mmol), 5-bromo-2-methyl-3-pentyn-2-ol (5.5 mg, 0.0309mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate=3:1, developed once) to give 3.3 mg of a product, to which wereadded tetrahydrofuran (0.5 ml) and 1M tetra-n-butylammonium fluoridesolution in tetrahydrofuran (0.3 ml). By the same procedure as inExample 33, the mixed solution was reacted (2 days) and worked up, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (1.17 mg, 43%).

IR(neat): 3400, 2920, 1455, 1370, 1250, 1170, 1055 cm⁻¹. ¹H NMR δ:0.74(s, 3H), 1.45(d, J=6.8 Hz, 3H), 1.48(s, 6H), 3.20(d, J=16.6 Hz, 1H),3.30(d, J=16.6 Hz, 1H), 3.56(q, J=6.8 Hz, 1H), 4.18-4.32(m, 1H),4.37-4.52(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.64(brs, 1H), 6.10(d,J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z: 442 (M⁺), 312 (100%). UVλ_(max) nm: 264.

Example 54 Preparation of1α,3β-dihydroxy-20(R)-{(E)-4-hydroxy-4-methyl-2-pentenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(5.0 mg, 0.00719 mmol), (E)-5-bromo-2-methyl-3-penten-2-ol (6.4 mg,0.0360 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol(0.5 ml) were reacted and worked up, and then the residue was purifiedby preparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate=3:1, developed once) to give 4.8 mg of a product, to which wereadded tetrahydrofuran (0.5 ml) and 1M tetra-n-butylammonium fluoridesolution in tetrahydrofuran (0.3 ml). By the same procedure as inExample 33, the mixed solution was reacted (2 days) and worked up, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed twice) togive the title compound as a colorless oil (1.88 mg, 59%).

IR(neat): 3400, 2920, 1450, 1370, 1205, 1140, 1050 cm⁻¹. ¹H NMR δ:0.73(s, 3H), 1.33(s, 6H), 1.44(d, j=6.8 Hz, 3H), 3.02-3.22(m, 2H),3.33(q, J=6.8 Hz, 1H), 4.16-4.31(m, 1H), 4.39-4.52(m, 1H), 5.01(brs,1H), 5.34(brs, 1H), 5.59(brs, 1H), 5.63-5.79(m, 2H), 6.10(d, J=11.2 Hz,1H), 6.38(d, J=11.2 Hz, 1H). MS m/z: 426 (M⁺-H₂O), 352(100%). UV λ_(max)nm: 264.

Example 55 Preparation of1α,3β-dihydroxy-20(R)-{(Z)-4-hydroxy-4-methyl-2-pentenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(4.8 mg, 0.00690 mmol),(Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene (10.1 mg, 0.0345mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:dichloromethaneethyl acetate=160:40:1, developed once) to give 4.2 mg of a product, towhich were added tetrahydrofuran (0.5 ml) and 1M tetra-n-butylammoniumfluoride solution in tetrahydrofuran (0.3 ml). By the same procedure asin Example 33, the mixed solution was reacted (2 days) and worked up,and then the residue was purified by preparative thin layerchromatography (0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1,developed twice) to give the title compound as a colorless oil (1.87 mg,61%).

IR(neat): 3400, 2920, 1450, 1370, 1200, 1140, 1055 cm⁻¹. ¹H NMR δ:0.73(s, 3H), 1.36(s, 6H), 1.48(d, J=6.9 Hz, 3H), 3.32-3.61(m, 3H),4.17-4.33(m, 1H), 4.37-4.52(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.37-5.63(m, 3H), 6.10(d,=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z:444(M⁺), 294(100%). UV λ_(max) nm: 264.

Example 56 Preparation of1α,3β-dihydroxy-20(R)-(4-ethyl-4-hydroxy-2-hexynylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(4.3 mg, 0.00619 mmol), 6-bromo-3-ethyl-4-hexyn-3-ol (6.4 mg, 0.0309mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate=3:1, developed once) to give 4.2 mg of a product, to which wereadded tetrahydrofuran (0.5 ml) and 1M tetra-n-butylammonium fluoridesolution in tetrahydrofuran (0.3 ml). By the same procedure as inExample 33, the mixed solution was reacted (2 days) and worked up, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (1.17 mg, 43%).

IR(neat): 3400, 2920, 1455, 1370, 1240, 1150, 1055 cm⁻¹. ¹H NMR δ:0.74(s, 3H), 1.03(t, J=7.3 Hz, 6H), 1.49(d, J=6.8 Hz, 3H), 1.66(q, J=7.3Hz, 4H), 3.23(d, J=16.6 Hz, 1H), 3.29(d, J=16.6 Hz, 1H), 3.59(q, J=6.8Hz, 1H), 4.18-4.33(m, 1H), 4.39-4.53(m, 1H), 5.01(brs, 1H), 5.34(brs,1H), 5.64(brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.34(d, J=11.2 Hz, 1H). MSm/z: 470 (M⁺), 312 (100%). UV λ_(max) nm: 264.

Example 57 Preparation of1α,3β-dihydroxy-20(R)-{(E)-4-ethyl-4-hydroxy-2-hexenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(5.0 mg, 0.00719 mmol), (E)-6-bromo-3-ethyl-4-hexen-3-ol (7.5 mg, 0.0360mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were reacted and worked up, and then the residue was purified bypreparative thin layer chromatography (0.25 mm×1, hexane:ethylacetate=3:1, developed once) to give 4.6 mg of a product, to which wereadded tetrahydrofuran (0.5 ml) and 1M tetra-n-butylammonium fluoridesolution in tetrahydrofuran (0.3 ml). By the same procedure as inExample 33, the mixed solution was reacted (2 days) and worked up, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed twice) togive the title compound as a colorless oil (2.40 mg, 71%).

IR(neat): 3400, 2920, 1450, 1370, 1220, 1140, 1055 cm⁻¹. ¹H NMR δ:0.73(s, 3H), 0.87(t, J=7.3 Hz, 6H), 1.44(d, J=6.8 Hz, 3H), 1.54(q, J=7.3Hz, 4H), 3.04-3.27(m, 2H), 3.35(q, J=6.8 Hz, 1H), 4.26-4.32(m, 1H),4.39-4.53(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.45-5.78(m, 3H),6.10(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z: 454(M⁺-H₂O),380(100%). UV λ_(max) nm: 264.

Example 58 Preparation of1α,3β-dihydroxy-20(R)-{(Z)-4-ethyl-4-hydroxy-2-hexenylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(5.0 mg, 0.00719 mmol), (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene(11.6 mg, 0.0360 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution inmethanol (0.5 ml) were reacted and worked up, and then the residue waspurified by preparative thin layer chromatography (0.25 mm×1,hexane:dichloromethane:ethyl acetate=160:40:1, developed once) to give4.2 mg of a product, to which were added tetrahydrofuran (0.5 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.3 ml). Bythe same procedure as in Example 33, the mixed solution was reacted (2days) and worked up, and then the residue was purified by preparativethin layer chromatography (0.25 mm×1, hexane:ethylacetate:ethanol=12:8:1, developed three times) to give the titlecompound as a colorless oil (1.74 mg, 51%).

IR(neat): 3400, 2925, 1450, 1365, 1210, 1055 cm⁻¹. ¹H NMR δ: 0.72(s,3H), 0.91(t, J=7.3 Hz, 6H), 1.48(d, J=6.8 Hz, 3H), 1.52(q, J=7.3 Hz,4H), 3.32-3.64(m, 3H), 4.16-4.32(m, 1H), 4.39-4.51(m, 1H), 5.01(brs,1H), 5.25-5.37(m, 2H), 5.50-5.69(m, 2H), 6.10(d, J=11.2 Hz, 1H), 6.38(d,J=11.2 Hz, 1H). MS m/z: 454(M⁺-H₂O), 312(100%). UV λ_(max) nm: 263.

Example 59 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-17α,20α-epoxypregna-5,7-diene PTADadduct

A mixed solution of 1α,3β-bis(tert-butyldimethylsilyloxy)pregna-5,7,17(Z)-triene PTAD adduct (1.00 g, 1.39 mmol) and sodiumbicarbonate (290 mg, 3.48 mmol) in dichloromethane (20 ml) was cooled at0° C. and combined with 70% m-chloroperbenzoic acid (412 mg, 1.67 mmol).The reaction mixture was stirred at the same temperature for 0.5 hour,then diluted with dichloromethane, washed with saturated aqueous sodiumbicarbonate solution, saturated aqueous sodium hydrogensulfite solution,saturated aqueous sodium bicarbonate solution and brine successively,and dried over magnesium sulfate. The solvent was distilled off underreduced pressure and the resulting residue was purified by columnchromatography (hexane:ethyl acetate=5:1) to give the title compound asa colorless solid (920 mg, 90%).

¹H-NMR δ: 0.08(s, 3H), 0.09(s, 3H), 0.11(s, 3H), 0.15(s, 3H), 0.89(s,9H), 0.91(s, 12H), 1.01(s, 3H), 1.41(d, 3H, J=5.6 Hz), 3.00(q, 1H, J=5.6Hz), 3.11-3.28(m, 1H), 3.85(brs, 1H), 4.69-4.85(m, 1H), 6.13(d, 1H,J=8.3 Hz), 6.28(d, 1H, J=7.9 Hz), 7.15(dd, 1H, J=7.3, 7.6 Hz), 7.28(dd,2H, J=7.6, 7.9 Hz), 7.38(d, 2H, J=7.6 Hz). UV λ_(max) nm: 260.

Example 60 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-17α,20α-epoxypregna-5,7-diene

In 1,3-dimethyl-2-imidazolidinone (60 ml) was dissolved1α,3β-bis(tert-butyldimethylsilyloxy)-17α,20α-epoxypregna-5,7-diene PTADadduct (613 mg, 0.835 mmol) and heated with stirring at 140° C. for 5hours. The reaction solution was taken into water, extracted with ethylacetate and washed with brine, then dried over anhydrous magnesiumsulfate. The solvent was distilled off under reduced pressure and theresulting residue was purified by column chromatography (hexane:ethylacetate=20:1) to give the title compound as a colorless solid (328 mg,70%).

¹H-NMR δ: 0.04(s, 9H), 0.08(s, 3H), 0.81(s, 3H), 0.86(s, 18H), 0.88(s,3H), 1.36(d, 3H, J=5.6 Hz), 2.95(q, 1H, J=5.6 Hz), 3.67(brs, 1H),3.95-4.10(m, 1H), 5.33-5.44(m, 1H), 5.57(d, 1H, J=5.3 Hz). UV λ_(max)nm: 269, 281, 293.

Example 61 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene

A solution of 1.5 M lithium diisopropylamide solution in cyclohexane(4.7 ml, 7.05 mmol) in toluene (3 ml) was cooled at 0° C. and combinedwith 0.95 M diethylaluminium chloride solution in hexane (4.95 ml, 4.70mmol). The reaction solution was stirred at the same temperature for 0.5hour, then stirred with a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-17α,20α-epoxypregna-5,7-diene (328mg, 0.587 mmol) in toluene (5 ml) at the same temperature for 3 hours,combined with saturated aqueous sodium bicarbonate solution and ethylacetate and filtered through Celite. The organic layer was washed withbrine and dried over magnesium sulfate, and the solvent was distilledoff under reduced pressure and the resulting residue was purified bycolumn chromatography (hexane:ethyl acetate=10:1) to give the titlecompound as a colorless solid (277 mg, 84%).

¹H-NMR δ: 0.05(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.88(s, 21H), 0.95(s,3H), 1.36(d, 3H, J=6.3 Hz), 3.71(brs, 1H), 3.97-4.12(m, 1H), 4.39(q, 1H,J=6.3 Hz), 5.35-5.44(m, 1H), 5.61(d, 1H, J=5.3 Hz), 5.67(s, 1H). UVλ_(max) nm: 270, 281, 293.

Example 62 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene

After a mixed solution of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(97 mg, 0.175mmol), sodium hydride (50 mg, 2.08 mmol) and4-bromo-2,3-epoxy-2-methylbutane (145 mg, 0.877 mmol) in tetrahydrofuran(2ml) was heated under reflux for 12 hours, 1M lithiumtri-s-butylborohydride solution in tetrahydrofuran (1.8 ml, 1.80 mmol)was added and the mixed solution was heated under reflux for 45 minutes.The reaction solution was stirred with 3N aqueous sodium hydroxidesolution and 30% aqueous hydrogen peroxide at room temperature for 30minutes, then diluted with ethyl acetate, washed with brine and driedover magnesium sulfate. The solvent was distilled off under reducedpressure and the resulting residue was purified by column chromatography(hexane:ethyl acetate=10:1) to give the title compound as a colorlessoil (113 mg, 100%).

IR(neat): 3500, 2960, 2860, 1463, 1375, 1260, 1105 cm⁻¹. ¹H-NMR δ:0.05(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.88(s, 21H), 0.94(s, 3H),1.23(s, 3H), 1.24(s, 3H), 1.31(d, 3H, J=6.6 Hz), 3.47-3.59(m, 1H),3.59-3.78(m, 1H), 3.70(brs, 1H), 3.93(q, 1H, J=6.6 Hz), 3.98-4.12(m,1H), 5.34-5.45(m, 1H), 5.57-5.70(m, 2H). UV λ_(max) nm: 269, 281, 293.

Example 63 Preparation of1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene

A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene(27 mg, 0.0419 mmol) in tetrahydrofuran (1 ml) was combined with 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.25 ml,0.25 mmol), and stirred at room temperature for 20 hours, then withheating under reflux for 2 hours. The reaction solution was diluted withethyl acetate and washed with saturated aqueous sodium bicarbonatesolution and brine successively, and the organic layer was dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was purified by preparative thin layerchromatography (0.5 mm×1 and 0.25 mm×1, dichloromethane:ethanol=20:1,developed twice) to give the title compound as a colorless oil (17.3 mg,99%).

IR(neat): 3420, 2940, 1735, 1660, 1460, 1365, 1270, 1150, 1055 cm⁻¹.¹H-NMR δ: 0.88(s, 3H), 0.96(s, 3H), 1.22(s, 3H), 1.23(s, 3H), 1.30(d,3H, J=6.6 Hz), 3.45-3.58(m, 1H), 3.58-3.72(m, 2H), 3.76(brs, 1H),3.94(q, 1H, J=6.6 Hz), 3.98-4.14(m, 1H), 5.37-5.48(m, 1H), 5.62(s, 1H),5.72(d, 1H, J=3.6 Hz). UV λ_(max) nm: 270, 281, 293.

Example 64 Preparation of1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutyloxy)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene(11 mg, 0.0264 mmol) and ethanol (200 ml), the reaction was performed bythe same procedure as in Example 15 (irradiation for 1 minute and 50seconds, and heating under reflux for 2 hours), and then the solvent wasdistilled off under reduced pressure and the resulting residue waspurified by preparative thin layer chromatography (0.25 mm×1,dichloromethane:ethyl acetate=20:1, developed twice, then 0.25 mm×0.5,hexane:ethyl acetate:ethanol=10:5:1, developed three times) to give thetitle compound as a colorless oil (0.890 mg, 8.1%).

IR(neat): 3400, 2980, 2940, 1450, 1370, 1160, 1060 cm⁻¹. ¹H-NMR δ:0.78(s, 3H), 1.23(s, 3H), 1.24(s, 3H), 1.31(d, 3H, J=6.6 Hz),3.47-3.58(m, 1H), 3.63(s, 1H), 3.61-3.73(m, 1H), 3.91(q, 1H, J=6.6 Hz),4.18-4.30(m, 1H), 4.39-4.51(m, 1H), 5.01(s, 1H), 5.34(s, 1H), 5.59(brs,1H), 6.10(d, 1H, J=11.6 Hz), 6.37(d, 1H, J=11.6 Hz). UV λ_(max) nm: 263.

Example 65 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20-oxopregna-5,7,16-triene

A suspension of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(600 mg, 1.07 mmol), pyridinium dichromate (610 mg, 1.61 mmol) andFlorisil (3 g) in dichloromethane (10 ml) was stirred at roomtemperature for 1.5 hours, then ultrasonicated for 2.5 hours. Thesolvent was distilled off under reduced pressure and the resultingresidue was diluted with diethyl ether and filtered through Celite. Thesolvent was distilled off under reduced pressure and the resultingresidue was purified by column chromatography (hexane:ethylacetate=15:1) to give the title compound as a colorless solid (343 mg,57%).

IR(KBr): 2920, 2850, 1655, 1585, 1460, 1370, 1250, 1225, 1100, 1075,1060 cm⁻¹. ¹H-NMR δ: 0.06(s, 6H), 0.07(s, 3H), 0.11(s, 3H), 0.87(s, 9H),0.89(s, 12H), 0.95(s, 3H), 2.28(s, 3H), 3.72(brs, 1H), 3.95-4.15(m, 1H),5.36-5.44(m, 1H), 5.57-5.67(m, 1H), 6.74(brs, 1H). MS m/z: 556(M⁺),367(100%). UV λ_(max) nm: 238, 270, 281, 293.

Example 66 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20-oxopregna-5,7,16-triene

A solution of1L,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(50.0 mg, 0.0894 mmol) and 4-methylmorpholine-N-oxide (15.7 mg, 0.134mmol) in dichloromethane (1 ml) was stirred with powdered molecularsieve 4A at room temperature for 10 minutes. This was combined withtetra-n-butylammonium perruthenate (1.6 mg, 0.00447 mmol) and stirred atroom temperature for 30 minutes. The reaction solution was filtered andthen diluted with dichloromethane, and the organic layer was washed withsaturated aqueous sodium bicarbonate solution, brine and saturatedaqueous copper sulfate solution successively and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure and theresulting residue was purified by preparative thin layer chromatography(0.5 mm×1, hexane:ethyl acetate=5:1, developed once) to give the titlecompound as a colorless solid (37.1 mg, 74%).

Example 67 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene

To a solution of1α,3β-bis(tert-butyldimethyl-silyloxy)-20-oxopregna-5,7,16-triene (93mg, 0.167 mmol) and cerium (III) chloride heptahydrate (93 mg, 0.251mmol) in methanol (1.5 ml) and tetrahydrofuran (6 ml) cooled at 0° C.was gradually added sodium borohydride (32 mg, 0.835 mmol). The reactionsolution was stirred at room temperature for one hour, then concentratedunder reduced pressure and the residue was taken into water andextracted with ethyl acetate. The organic layer was washed with brineand then dried over magnesium sulfate, and the solvent was distilled offunder reduced pressure. The resulting residue was purified bypreparative thin layer chromatography (0.5 mm×2, hexane:ethylacetate=10:1, developed three times) to give the title compound as acolorless solid (68.2 mg, 73%) and1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(17.0 mg, 18%).

Title compound: ¹H-NMR δ: 0.05(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.85(s,3H), 0.89(s, 18H), 0.95(s, 3H), 1.37(d, 3H, J=6.6 Hz), 3.70(brs, 1H),3.96-4.12(m, 1H), 4.31-4.44(m, 1H), 5.31-5.43(m, 1H), 5.61(d, 1H, J=5.3Hz), 5.66(brs, 1H). UV λ_(max) nm: 270, 281, 293.

Example 68 Preparation of1α,3βbis(tert-butyldimethylsilyloxy)-20(R)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene

A mixed solution of1α,3β-bis(tert-butyldimethyl-silyloxy)-20(R)-hydroxypregna-5,7,16-triene(51 mg, 0.0911 mmol), sodium hydride (50 mg, 2.08 mmol) and4-bromo-2,3-epoxy-2-methylbutane (75 mg, 0.455 mmol) in tetrahydrofuran(2ml) was heated under reflux for 1.5 hours and combined with 1M lithiumtri-s-butylborohydride solution in tetrahydrofuran (0.9 ml, 0.900 mmol),and the mixed solution was heated under reflux for 20 minutes. Thereaction solution was stirred with 3N aqueous sodium hydroxide solutionand 30% aqueous hydrogen peroxide at room temperature for 30 minutes,then diluted with ethyl acetate, washed with brine and dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the resulting residue was purified by preparative thin layerchromatography (0.5 mm×1, hexane:ethyl acetate=10:1, developed twice) togive the title compound as a colorless oil (48.6 mg, 83%).

IR(neat): 3500, 2950, 2870, 1470, 1380, 1260 cm⁻¹. ¹H-NMR δ: 0.05(s,3H), 0.06(s, 3H), 0.07(s, 3H), 0.11(s, 3H), 0.85(s, 3H), 0.88(s, 18H),0.94(s, 3H), 1.23(s, 3H), 1.24(s, 3H), 1.32(d, 3H, J=6.6 Hz), 1.73(t,2H, J=5.6 Hz), 3.53(s, 1H), 3.57-3.70(m, 2H), 3.70(brs, 1H),3.93-4.11(m, 2H), 5.31-5.42(m, 1H), 5.60(d, 1H, J=5.6 Hz), 5.64(s, 1H).UV λ_(max) nm: 270, 281, 293.

Example 69 Preparation of1α,3βdihydroxy-20(R)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene

A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(3-hydroxy-3-methylbutyloxy)pregna-5,7,16-triene(50 mg, 0.0775 mmol) in tetrahydrofuran (1 ml) was combined with 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.5 ml) andstirred at room temperature for 12 hours, then with heating under refluxfor 5 hours. The reaction solution was diluted with ethyl acetate andwashed with saturated aqueous sodium bicarbonate solution and brinesuccessively, and the organic layer was dried over magnesium sulfate.The solvent was distilled off under reduced pressure and the resultingresidue was purified by preparative thin layer chromatography (0.5 mm×2,dichloromethane:ethanol=20:1, developed twice) to give the titlecompound as a colorless oil (23.8 mg, 74%) and recovered raw materials(6 mg, 12%).

IR(neat): 3420, 2970, 2940, 1460, 1370, 1160, 1088, 1060 cm⁻¹. ¹H-NMR δ:0.84(s, 3H), 0.97(s, 3H), 1.23(s, 3H), 1.24(s, 3H), 1.73(d, 3H, J=6.6Hz), 3.59-3.72(m, 3H), 3.77(brs, 1H), 4.00(q, 1H, J=6.6 Hz),4.06-4.20(m, 1H), 5.41-5.51(m, 1H), 5.65(s, 1H), 5.73(d, 1H, J=4.0 Hz).UV λ_(max) nm: 270, 281, 292.

Example 70 Preparation of1α,3β-dihydroxy-20(R)-(3-hydroxy-3-methylbutyloxy)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(R)-(3-hydroxy-3-methyl-butyloxy)pregna-5,7,16-triene(12.2 mg, 0.0293 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 1 minute and 30seconds, and heating under reflux for 2 hours), and then the solvent wasdistilled off under reduced pressure and the resulting residue waspurified by preparative thin layer chromatography (0.25 mm×1,dichloromethane:ethanol=10:1, developed once, then 0.25 mm×0.5,hexane:ethyl acetate:ethanol=10:5:1, developed three times) to give thetitle compound as a colorless oil (1.11 mg, 9.1%).

IR(neat): 3380, 2940, 2850, 1370, 1160, 1055 cm⁻¹. ¹H-NMR δ: 0.75(s,3H), 1.23(s, 3H), 1.24(s, 3H), 1.32(d, 3H, J=6.6 Hz), 1.75(t, 2H, J=5.9Hz), 3.58(s, 1H), 3.65(t, 2H, J=5.9 Hz), 3.97(q, 1H, J=6.6 Hz),4.20-4.25(m, 1H), 4.40-4.51(m, 1H), 5.00(s, 1H), 5.33(s, 1H), 5.62(s,1H), 6.10(d, 1H, J=11.6 Hz), 6.37(d, 1H, J=11.6 Hz). UV λ_(max) nm: 264.

Example 71 Preparation of1α,3β-dihydroxy-20(S)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 3,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(6.8 mg, 0.00978 mmol), 1,2-epoxy-2-ethylbutane (9.8 mg, 0.0978 mmol),tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) werereacted and then concentrated under reduced pressure. The residue wasdiluted with ethyl acetate, washed with water and brine successively anddried over magnesium sulfate. The solvent was removed under reducedpressure and the resulting residue was purified by preparative thinlayer chromatography (0.25 mm×1, hexane:ethyl acetate=4:1, developedonce) to give a fraction containing1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.This was reacted with tetrahydrofuran (2 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (1 ml) (60°C., 1.5 hours) and worked up by the same procedure as in Example 9, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (2.05 mg, 47%).

IR(neat): 3369, 2964, 2929, 2879, 2848, 1446, 1369, 1055 cm⁻¹. ¹H-NMR δ:0.84(s, 3H), 1.42(d, J=7.3 Hz, 3H), 2.76-2.87(m, 1H), 3.43(q, J=6.8 Hz,1H), 4.18-4.30(m, 1H), 4.38-4.50(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.62(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). UVλ_(max) nm: 263.

Example 72 Preparation of1α,3β-dihydroxy-20(R)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 71, l1t,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(6.9 mg, 0.00993 mmol), 1,2-epoxy-2-ethylbutane (9.9 mg, 0.0993 mmol),tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml) weresubjected to alkylation reaction and worked up, and then the residue waspurified by preparative thin layer chromatography (0.25 mm×1,hexane:ethyl acetate=4:1, developed once) to give a fraction containing1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.This was reacted with tetrahydrofuran (2 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (1 ml) (60°C., 1.5 hours) and worked up by the same procedure as in Example 9, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (2.64 mg, 59%).

IR(neat): 3369, 2929, 2909, 2879, 2848, 1446, 1371, 1055 cm⁻¹. ¹H-NMR δ:0.73(s, 3H), 0.87(t, J=7.4 Hz, 3H), 0.88(t, J=7.4 Hz, 3H), 1.46(d, J=6.9Hz, 3H), 2.77-2.87(m, 1H), 3.35(q, J=6.9 Hz, 1H), 4.18-4.31(m, 1H),4.39-4.01(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.59(brs, 1H), 6.10(d,J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). UV λ_(max) nm: 263.

Example 73 Preparation of1α,3β-dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 71,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(5.7 mg, 0.00820 mmol), (S)-(+)-1,2-epoxy-3-methylbutane (3.53 mg,0.0410 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol(0.5 ml) were subjected to alkylation reaction and worked up, and thenthe residue was purified by preparative thin layer chromatography (0.25mm×1, hexane:ethyl acetate=3:1, developed once) to give a fractioncontaining1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{2(S)-hydroxy-3-methylbutylthio}-9,10-secopregna-5,7,10(19),16-tetraene.This was reacted with tetrahydrofuran (0.5 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.3 ml) (60°C., 2 hours) and worked up by the same procedure as in Example 9, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (1.36 mg, 38%).

IR(neat): 3400, 2950, 2920, 2860, 2845, 1450, 1370, 1050 cm⁻¹. ¹H-NMR δ:0.85(s, 3H), 0.93(d, J=7.4 Hz, 3H), 0.96(d, J=7.4 Hz, 3H), 1.43(d, J=6.9Hz, 3H), 2.53-2.66(m, 1H), 2.73(dd, J=13.4, 3.2 Hz, 1H), 2.76-2.88(m,1H), 3.32-3.54(m, 2H), 4.16-4.30(m, 1H), 4.38-4.51(m, 1H), 5.01(brs,1H), 5.34(brs, 1H), 5.64(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d,J=11.2 Hz, 1H). UV λ_(max) nm: 263.

Example 74 Preparation of1α,3β-dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 71,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(5.1 mg, 0.00734 mmol), (R)-(−)-1,2-epoxy-3-methylbutane (3.16 mg,0.0367 mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol(0.5 ml) were subjected to alkylation reaction and worked up, and thenthe residue was purified by preparative thin layer chromatography (0.25mm×1, hexane:ethyl acetate=3:1, developed once) to give a fractioncontaining1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{2(R)-hydroxy-3-methylbutylthio}-9,10-secopregna-5,7,10(19),16-tetraene.This was reacted with tetrahydrofuran (0.5 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.3 ml) (60°C., 2 hours) and worked up by the same procedure as in Example 9, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (1.34 mg, 42%).

IR(neat), 3400, 2958, 2929, 2850, 1446, 1369, 1254, 1213, 1053 cm⁻¹.¹H-NMR δ: 0.81(s, 3H), 0.92(d, J=6.8 Hz, 3H), 0.96(d, J=6.8 Hz, 3H),1.41(d, J=6.8 Hz, 3H), 2.56-2.66(m, 1H), 2.70(dd, J=13.4, 2.8 Hz, 1H),2.76-2.88(m, 1H), 3.31-3.42(m, 1H), 3.51(q, J=6.8 Hz, 1H), 4.18-4.30(m,1H), 4.39-4.50(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.61(brs, 1H),6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). UV λ_(max) nm: 264.

Example 75 Preparation of1α,3β-dihydroxy-20(R)-{2(S)-hydroxy-3-methylbutylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 71,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(7.1 mg, 0.0102 mmol), (S)-(+)-1,2-epoxy-3-methylbutane (4.4 mg, 0.0510mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were subjected to alkylation reaction and worked up, and then theresidue was purified by preparative thin layer chromatography (0.25mm×1, hexane:ethyl acetate=4:1, developed once) to give a fractioncontaining1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{2(S)-hydroxy-3-methylbutylthio}-9,10-secopregna-5,7,10(19),16-tetraene.This was reacted with tetrahydrofuran (0.5 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.3 ml) (60°C., 2 hours) and worked up by the same procedure as in Example 9, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (1.24 mg, 28%).

IR(neat), 3367, 2956, 2929, 2850, 1446, 1369, 1215, 1055 cm⁻¹. ¹H-NMR δ:0.75(s, 3H), 0.93(d, J=6.9 Hz, 3H), 0.96(d, J=6.9 Hz, 3H), 1.46(d, J=6.9Hz, 3H), 2.56-2.66(m, 1H), 2.74(dd, J=13.2, 3.0 Hz, 1H), 2.78-2.88(m,1H), 3.32-3.48(m, 2H), 4.16-4.29(m, 1H), 4.38-4.50(m, 1H), 5.01(brs,1H), 5.34(brs, 1H), 5.60(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d,J=11.2 Hz, 1H). UV λ_(max) nm: 263.

Example 76 Preparation of1α,3β-dihydroxy-20(R)-{2(R)-hydroxy-3-methylbutylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Under the same conditions as in Example 71,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(6.7 mg, 0.00964 mmol), (R)-(−)-1,2-epoxy-3-methylbutane (4.2 mg, 0.0482mmol), tetrahydrofuran (0.5 ml) and 1M KOH solution in methanol (0.5 ml)were subjected to alkylation reaction and worked up, and then theresidue was purified by preparative thin layer chromatography (0.25mm×1, hexane:ethyl acetate=4:1, developed once) to give a fractioncontaining1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{2(R)-hydroxy-3-methylbutylthio}-9,10-secopregna-5,7,10(19),16-tetraene.This was reacted with tetrahydrofuran (0.5 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.3 ml) (60°C., 2 hours) and worked up by the same procedure as in Example 9, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give the title compound as a colorless oil (0.754 mg, 18%).

IR(neat), 3340, 2922, 2846, 1456, 1369, 1290, 1238, 1043 cm⁻¹. ¹H-NMR δ:0.72(s, 3H), 0.94(d, J=6.9 Hz, 3H), 0.97(d, J=6.9 Hz, 3H), 1.47(d, J=6.9Hz, 3H), 2.56-2.68(m, 1H), 2.75-2.88(m, 2H), 3.32-3.45(m, 2H),4.18-4.30(m, 1H), 4.39-4.50(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.61(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). UVλ_(max) nm: 263.

Example 77 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(S)-hydroxypentylthio}pregna-5,7,16-trieneand1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(R)-hydroxypentylthio}pregna-5,7,16-triene

Under the same conditions as in Example 71,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(151.7 mg, 0.220 mmol), 1,2-epoxy-3-ethylpentane (503 mg, 4.40 mmol),tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) weresubjected to alkylation reaction and worked up, and then the residue waspurified by preparative thin layer chromatography (0.5 mm×3,hexane:ethyl acetate=4:1, developed once) to give1α,3β-bis(tert-butyldimethyl-silyloxy)-20(S)-(3-ethyl-2-hydroxypentylthio)pregna-5,7,16-triene(diastreomer mixture). This was dissolved in dichloromethane (2 ml) andstirred with 4-dimethylaminopyridine (117 mg, 0.956 mmol) and(1R)-(+)-camphanic chloride (104 mg, 0.478 mmol) at room temperature for15 minutes, and then the solvent was distilled off under reducedpressure. The residue was diluted with ethyl acetate, washed withice-cooled 0.5 N hydrochloric acid, saturated aqueous sodium bicarbonatesolution and brine successively and dried over magnesium sulfate. Thesolvent was removed under reduced pressure and the residue was purifiedby preparative thin layer chromatography (0.5 mm×4, hexane:benzene:ethylacetate=10:20:1, developed three times) to separate low-polarity andhigh-polarity components. Each component was then dissolved intetrahydrofuran (3 ml) and stirred with 1 M sodium methoxide solution inmethanol (1 ml) at room temperature for 2 hours, and the solvent wasdistilled off under reduced pressure. The residue was diluted with ethylacetate, washed with water and brine successively and dried overmagnesium sulfate. The solvent was removed under reduced pressure andthe resulting residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=4:1, developed once) togive1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(S)-hydroxypentylthio}pregna-5,7,16-trieneas a colorless oil (57.9 mg, 44%) and1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(R)-hydroxypentylthio}pregna-5,7,16-trieneas a colorless oil (56.7 mg, 43%).

1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(S)-hydroxypentylthio}pregna-5,7,16-triene:

IR(neat): 2897, 2856, 1462, 1371, 1254, 1099, 1082 cm⁻¹. ¹H-NMR δ:0.05(s, 3H), 0.06(s, 6H), 0.11(O, 3H), 0.88(s, 18H), 1.44(d, J=6.9 Hz,3H), 2.47(dd, J=13.4, 9.6 Hz, 1H), 2.72(dd, J=13.4, 3.0 Hz, 1H),2.79-2.91(m, 1H), 3.49(q, J=6.7 Hz, 1H), 3.60-3.73(m, 2H), 3.95-4.13(m,1H), 5.34-5.42(m, 1H), 5.56-5,62(m, 1H), 5.66(brs, 1H). MS m/z:557(M⁺-OSi ^(t)BuMe₂), 500(100%). UV λ_(max) nm: 270, 281, 293.

1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(R)-hydroxypentylthio}pregna-5,7,16-triene:

IR(neat): 2956, 2929, 2856, 1462, 1371, 1254, 1099, 1082 cm⁻¹. ¹H-NMRδ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.89(s, 18H), 1.43(d, J=6.9 Hz,3H), 2.68(dd, J=13.2, 3.0 Hz, 1H), 2.78-2.92(m, 1H), 3.53(q, J=6.8 Hz ,1H), 3.56-3.66(m, 1H), 3.71(brs, 1H), 3.95-4.12(m, 1H), 5.31-5.44(m,1H), 5.52-5.68(m, 2H). MS m/z: 557(M⁺-Osi ^(t)BuMe₂), 500(100%). UVλ_(max) nm: 270, 281, 293.

Example 78 Preparation of1α,3β-dihydroxy-20(S)-{3-ethyl-2(S)-hydroxypenty}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(S)-hydroxypentylthio}pregna-5,7,16-triene(55.3 mg, 0.0802 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×2,dichloromethane:ethanol=9:1, developed once) to give the title compoundas a white solid (35.5 mg, 96%).

IR(KBr): 3390, 2950, 2920, 2870, 1460, 1365, 1045, 1030, 1020 cm⁻¹. ¹HNMR (CDCl₃/CD₃OD) δ: 0.91(t, J=7.3 Hz, 6H), 0.94(s, 3H), 0.97(s, 3H),1.44(d, J=6.9 Hz, 3H), 2.68(dd, J=13.4, 3.5 Hz, 1H), 2.78-2.90(m, 1H),3.43-3.73(m, 2H), 3.75(brs, 1H), 3.92-4.08(m, 1H), 5.40-5.49(m, 1H),5.66(brs, 1H), 5.68-5.76(m, 1H). MS m/z: 460(M⁺), 315(100%). UV λ_(max)nm: 270, 281, 293.

Example 79 Preparation of1α,3β-dihydroxy-20(S)-{3-ethyl-2(R)-hydroxypentylthio}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{3-ethyl-2(R)-hydroxypentylthio}pregna-5,7,16-triene(54.9 mg, 0.0797 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×2,dichloromethane:ethanol=9:1, developed once) to give the title compoundas a colorless oil (37.9 mg, 100%).

IR(neat): 3400, 2962, 2929, 2873, 1460, 1369, 1055, 1030 cm⁻¹. ¹H-NMR δ:0.90(t, J=7.3 Hz, 6H), 0.92(s, 3H), 0.98(s, 3H), 1.43(d, J=6.9 Hz, 3H),2.68(dd, J=13.5, 3.0 Hz, 1H), 2.75-2.87(m, 1H), 3.55(q, J=6.9 Hz, 1H),3.56-3.67(m, 1H), 3.79(brs, 1H), 3.99-4.16(m, 1H), 5.41-5.50(m, 1H),5.63(brs, 1H), 5.70-5.79(m, 1H). MS m/z: 460 (M^(+),) 313 (100%). UVλ_(max) nm: 270, 281, 293.

Example 80 Preparation of1α,3β-dihydroxy-20(S)-{3-ethyl-2(S)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{3-ethyl-2(S)-hydroxypentylthio}pregna-5,7,16-triene(33.0 mg, 0.0716 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.25 minutes and heating under reflux for 2 hours) and work up wereperformed by the same procedure as in Example 15, and then the residuewas purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=14:6:1, developed twice, then 0.25mm×1, hexane:ethyl acetate:ethanol 10:10:1, developed three times) togive the title compound as a colorless oil (1.81 mg, 5.5%).

IR(neat): 3367, 2960, 2873, 1456, 1369, 1055 cm⁻¹. ¹H NMR δ: 0.85(s,3H), 0.90(t, J=7.3 Hz, 6H), 1.43(d, J=6.9 Hz, 3H), 2.47(dd, J=13.3, 9.6Hz, 1H), 2.55-2.68(m, 1H), 2.71(dd, J=13.3, 3.0 Hz, 1H), 2.78-2.89(m,1H), 3.47(q, J=6.8 Hz, 1H), 3.60-3.72(m, 1H), 4.19-4.31(m, 1H),4.40-4.51(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.64(brs, 1H), 6.10(d,J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z: 460(M⁺), 312(100%). UVλ_(max) nm: 263.

Example 81 Preparation of1α,3β-dihydroxy-20(S)-{3-ethyl-2(R)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{3-ethyl-2(R)-hydroxy-pentylthio}pregna-5,7,16-triene(34.1 mg, 0.0740 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.25 minutes and heating under reflux for 2 hours) and work up wereperformed by the same procedure as in Example 15, and then the residuewas purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=10:10:1, developed twice, then0.25 mm×1, dichloromethane:ethanol=18:1, developed three times) to givethe title compound as a colorless oil (2.13 mg, 6.2%).

IR(neat): 3369, 2960, 2929, 2873, 1446, 1369, 1055 cm⁻¹. ¹H NMR δ:0.82(s, 3H), 0.90(t, J=7.1 Hz, 6H), 1.42(d, J=6.9 Hz, 3H), 2.75-2.89(m,1H), 3.51(q, J=6.9 Hz, 1H), 3.57-3.68(m, 1H), 4.18-4.31(m, 1H),4.39-4.50(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.60(brs, 1H), 6.11(d,J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z: 460(M⁺), 312(100%). UVλ_(max) nm: 263.

Example 82 Preparation of1α,3β-dihydroxy-20(R)-{3-ethyl-2(R)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraeneand1α,3β-dihydroxy-20(R)-{3-ethyl-2(S)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraene

By the same procedure as in Example 71,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-phenoxycarbonylthio-9,10-secopregna-5,7,10(19),16-tetraene(24.5 mg, 0.0352 mmol), 1,2-epoxy-3-ethylpentane (80.4 mg, 0.704 mmol),tetrahydrofuran (1 ml) and 1M KOH solution in methanol (1 ml) weresubjected to alkylation reaction (room temperature, one hour) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×1, hexane:ethyl acetate=4:1, developed once) togive1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(3-ethyl-2-hydroxy-pentylthio)-9,10-secopregna-5,7,10(19),16-tetraene(diastreomer mixture, 18.5 mg). An aliquot of 17.2 mg was dissolved indichloromethane (1 ml) and stirred with 4-dimethylaminopyridine (15.3mg, 0.125 mmol) and (1S)-(−)-camphanic chloride (13.5 mg, 0.0625 mmol)at room temperature for 15 minutes, and then the solvent was distilledoff under reduced pressure. The residue was diluted with ethyl acetate,washed with ice-cooled 0.5 N hydrochloric acid, saturated aqueous sodiumbicarbonate solution and brine successively and dried over magnesiumsulfate. The solvent was removed under reduced pressure and the residuewas purified by preparative thin layer chromatography (0.5 mm×1,hexane:benzene:ethyl acetate=10:20:1, developed twice) to separatelow-polarity and high-polarity components. Each component was thendissolved in tetrahydrofuran (1 ml) and stirred with 1 M sodiummethoxide solution in methanol (0.5 ml) at room temperature for 2 hours,and the solvent was distilled off under reduced pressure. The residuewas diluted with ethyl acetate, washed with water and brine successivelyand dried over magnesium sulfate. The solvent was removed under reducedpressure and the resulting residue was purified by preparative thinlayer chromatography (0.5 mm×1, hexane:ethyl acetate=4:1, developedonce) to give1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{3-ethyl-2(R)-hydroxypentyl-thio}-9,10-secopregna-5,7,10(19),16-tetraeneand1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{3-ethyl-2(S)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraene.Each compound was reacted with tetrahydrofuran (1 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.5 ml) (60°C., 2 hours) and worked up by the same procedure as in Example 9, andthen the residue was purified by preparative thin layer chromatography(0.25 mm×1, hexane:ethyl acetate:ethanol=12:8:1, developed three times)to give1α,3β-dihydroxy-20(R)-{3-ethyl-2(R)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraeneas a colorless oil (3.09 mg, 20%) and1α,3β-dihydroxy-20(R)-{3-ethyl-2(S)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraeneas a colorless oil (2.95 mg, 20%).

1α,3β-dihydroxy-20(R)-{3-ethyl-2(R)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraene:

IR(neat): 3361, 2960, 2929, 2873, 1446, 1371, 1290, 1217, 1055 cm⁻¹. ¹HNMR δ: 0.72(s, 3H), 0.91(t, J=7.1 Hz, 6H), 1.47(d, J=6.9 Hz, 3H),2.54-2.67(m, 1H), 2.72-2.90(m, 2H), 3.37(q, J=6.9 Hz, 1H), 3.58-3.70(m,1H), 4.18-4.29(m, 1H), 4.38-4.50(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.61(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z:460(M⁺), 312(100%). UV λ_(max) nm: 263.

1α,3β-dihydroxy-20(R)-{3-ethyl-2(S)-hydroxypentylthio}-9,10-secopregna-5,7,10(19),16-tetraene:

IR(neat): 3369, 2960, 2929, 2873, 1448, 1371, 1290, 1211, 1055 cm⁻¹. ¹HNMR δ: 0.75(s, 3H), 0.90(t, J=7.1 Hz, 6H) 1.46(d, J=6.9 Hz, 3H),2.48(dd, J=13.5, 9.6 Hz, 1H), 2.55-2.66(m, 1H), 2.72(dd, J=13.5, 3.1 Hz,1H), 2.76-2.88(m, 1H), 3.41(q, J=6.9 Hz, 1H), 3.57-3.70(m, 1H),4.18-4.30(m, 1H), 4.38-4.50(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.60(brs, 1H), 6.10(d, J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). MS m/z:460(M⁺), 312(100%). UV λ_(max) nm: 263.

Example 83 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy)pregna-5,7,16-triene

A solution of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne(109 mg, 0.375 mmol) in tetrahydrofuran (1 ml) was stirred at 60° C. for2 hours. The solution was cooled to room temperature and then taken intowater and extracted with ethyl acetate. The extract was washed withbrine and dried over magnesium sulfate, and the solvent was distilledoff under reduced pressure. The resulting residue was purified bypreparative thin layer chromatography (0.5 mm×2, hexane:ethylacetate=40:1, developed once) to give the title compound as a colorlessoil (82.4 mg, 99%).

IR(neat): 2950, 2875, 1460, 1370, 1250, 1160, 1090, 1040 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.67(q, J=7.8 Hz, 6H), 0.89(s, 18H), 0.96(t, J=7.8 Hz, 9H), 1.32(d, J=6.5 Hz, 3H), 1.46(s, 6H), 3.70(brs,1H), 3.76-3.83(m, 1H), 3.94-4.39(m, 3H), 5.35-5.44(m, 1H), 5.56-5.66(m,2H). UV λ_(max) nm: 270, 281, 293.

Example 84 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene(116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) togive the title compound as a colorless oil (85.9 mg, 99%).

IR(neat): 2950, 2850, 1460, 1370, 1250, 1150, 1040 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.57(q, J=7.8 Hz, 6H), 0.89(s, 18H), 0.94(t, J=7.8 Hz, 9H), 1.31(s, 6H), 3.72(brs, 1H), 3.79-4.18(m, 4H),5.37-5.45(m, 1H), 5.57-5.83(m, 4H). UV λ_(max) nm: 270, 281, 293.

Example 85 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene(125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) togive the title compound as a colorless oil (80.7 mg, 98%).

IR(neat): 2950, 2850, 1460, 1370, 1255, 1170, 1100, 1040 cm⁻¹. ¹H NMR δ:0.05(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.58(q, J=7.8 Hz, 6H), 0.88(s, 18H), 0.94(t, J=7.8 Hz, 9H), 1.32(s, 6H), 3.71(brs, 1H), 3.93-4.14(m, 2H),4.16-4.36(m, 2H), 5.29-5.44(m, 3H), 5.57-5.66(m, 2H). UV λ_(max) nm:270, 281, 293.

Example 86 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol),15-crown-5 (10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up,and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) togive the title compound as a colorless oil (79.0 mg, 92%).

IR(neat): 2950, 2850, 1460, 1375, 1255, 1080, 1010 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.67(q, J=7.8 Hz, 6H), 0.89(s, 18H), 1.32(d, J=6.4 Hz, 3H), 3.72(brs, 1H), 3.95-4.32(m, 4H), 5.36-5.44(m,1H), 5.58-5.68(m, 2H). MS m/z: 796(M⁺), 278(100%). UV λ_(max) nm: 270,281, 293.

Example 87 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and (E)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene(134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) togive the title compound as a colorless oil (86.0 mg, 100%).

IR(neat): 2950, 2850, 1460, 1375, 1255, 1100, 1000 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.58(q, J=7.8 Hz, 6H), 0.89(s, 18H), 1.31(d, J=6.6 Hz, 3H), 3.71(brs, 1H), 3.70-4.19(m, 4H), 5.37-5.45(m,1H), 5.49-5.76(m, 4H). UV λ_(max) nm: 270, 281, 293.

Example 88 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5, 7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene(103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) togive the title compound as a colorless oil (83.6 mg, 98%).

IR(neat): 2950, 2850, 1460, 1370, 1250, 1100, 1000 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.60(q, J=7.5 Hz, 6H), 0.89(s,18H), 1.32(d, J=6.6 Hz, 3H), 3.71(brs, 1H), 3.89-4.47 (m, 4H),5.09-5.20(m, 1H), 5.35-5.66(m, 4H). MS m/z: 798(M⁺), 277(100%). UVλ_(max) nm: 270, 281, 293.

Example 89 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy)pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and 1-bromo-4-methyl-4-triethylsilyloxy-2-pentyne(109 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) togive the title compound as a colorless oil (76.4 mg, 93%).

IR(neat): 2950, 2850, 1465, 1375, 1250, 1160, 1090, 1040 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.67(q, J=7.8 Hz, 6H), 0.85(s,3H), 0.89(s, 18H), 0.95(s, 3H), 0.96(t, J=7.8 Hz, 9H), 1.33(d, J=6.6 Hz,3H), 1,48(s, 6H), 3.71(brs, 1H), 3.93-4.32(m, 4H), 5.36-5.45(m, 1H),5.58-5.66(m, 1H), 5.60(brs, 1H). UV λ_(max) nm: 270, 281, 293.

Example 90 Preparation of 1α,362-bis(tert-butyldimethylsilyloxy)-20(R)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and (E)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene(116 mg, 0.375 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) togive the title compound as a colorless oil (73.4 mg, 89%).

IR(neat): 2950, 2850, 1460, 1370, 1250, 1150, 1095, 1040 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.58(q, J=7.8 Hz, 6H), 0.85(s,3H), 0.88(s, 9H), 0.89(s, 9H), 0.94(t, J=7.8 Hz, 9H), 0.94(s, 3H),1.30(s, 6H), 1.33(d, J=5.1 Hz, 3H), 3.71(brs, 1H), 3.83-4.16(m, 4H),5.35-5.45(m, 1H), 5.57-5.88(m, 4H). UV λ_(max) nm: 270, 281, 293.

Example 91 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and (Z)-1-bromo-4-methyl-4-triethylsilyloxy-2-pentene(125 mg, 0.428 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=30:1, developed once) togive the title compound as a colorless oil (70.3 mg, 85%).

IR(neat): 2950, 2850, 1460, 1375, 1255, 1170, 1100, 1040 cm⁻¹. ¹H NMR δ:0.06(s, 3H), 0.07(s, 6H), 0.11(s, 3H), 0.59(q, J=7.9 Hz, 6H), 0.86(s,3H), 0.88(s, 9H), 0.89(s, 9H), 0.95(t, J=7.9 Hz, 9H), 0.95(s, 3H),1.32(s, 6H), 1.33(d, J=4.9 Hz, 3H), 3.71(brs, 1H), 3.96-4.13(m, 2H),4.23-4.38(m, 2H), 5.29-5.47(m, 3H), 5.58-5.68(m, 2H). UV λ_(max) nm:270, 281, 293.

Example 92 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene(58.9 mg, 0.105 mmol), sodium hydride (60%, 21.0 mg, 0.525 mmol),15-crown-5 (10 μl) and 1-bromo-4-ethyl-4-triethylsilyloxy-2-hexyne (134mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and worked up,and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=19:1, developed once) togive the title compound as a colorless oil (60.2 mg, 72%).

IR(neat): 2950, 2850, 1460, 1370, 1250, 1085 cm⁻¹. ¹H NMR δ: 0.06(s,3H), 0.07(s, 6H), 0.11(s, 3H), 0.67(q, J=7.3 Hz, 6H), 0.88(s, 9H),0.89(s, 9H), 1.33(d, J=6.6 Hz, 3H), 3.71(brs, 1H), 3.97-4.35(m, 4H),5.35-5.44(m, 1H), 5.58-5.64(m, 1H), 5.67(brs, 1H). MS m/z: 796(M⁺),301(100%). UV λ_(max) nm: 270, 281, 293.

Example 93 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and (E)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene(134 mg, 0.420 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) togive the title compound as a colorless oil (62.4 mg, 73%).

IR(neat): 2950, 2870, 1460, 1375, 1255, 1070 cm⁻¹. ¹H NMR δ: 0.06(s,3H), 0.07(s, 6H), 0.11(s, 3H), 0.58(q, J=7.8 Hz, 6H), 0.88(s, 9H),0.89(s, 9H), 1.32(d, J=6.6 Hz, 3H), 3.71(brs, 1H), 3.88-4.14(m, 4H),5.36-5.44(m, 1H), 5.54-5.76(m, 4H). MS m/z: 798(M⁺), 609(100%). UVλ_(max) nm: 270 281, 293.

Example 94 Preparation of1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene

Under the same conditions as in Example 83,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene(60.0 mg, 0.107 mmol), sodium hydride (60%, 17.1 mg, 0.428 mmol),15-crown-5 (10 μl) and (Z)-1-bromo-4-ethyl-4-triethylsilyloxy-2-hexene(103 mg, 0.321 mmol) were reacted in tetrahydrofuran (1 ml) and workedup, and then the residue was purified by preparative thin layerchromatography (0.5 mm×2, hexane:ethyl acetate=40:1, developed once) togive the title compound as a colorless oil (84.6 mg, 99% ).

IR(neat): 2950, 2850, 1460, 1375, 1255, 1100, 1070 cm⁻¹. ¹H NMR δ:0.05(s, 3H), 0.06(s, 6H), 0.11(s, 3H), 0.61(q, J=7.8 Hz, 6H), 0.88(s,9H), 0.89(s, 9H), 1.32(d, J=6.6 Hz, 3H), 3.71(brs, 1H), 4.15-4.24(m,2H), 4.23-4.38(m, 2H), 5.13(dt, J=12.5, 2.2 Hz, 1H), 5.35-5.42(m, 1H),5.50(dt, J=12.2, 5.0 Hz, 1H), 5.59-5.69(m, 2H). MS m/z: 798(M⁺),610(100%). UV λ_(max) nm: 270, 281, 293.

Example 95 Preparation of1α,3β-dihydroxy-20(S)-(4-hydroxy-4-methyl-2-pentynyloxy)pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy)pregna-5,7,16-triene(80.0 mg, 0.104 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a pale yellow oil (14.0 mg, 32%).

IR(neat): 3400, 2980, 2940, 2850, 1450, 1370, 1230, 1170, 1060 cm⁻¹. ¹HNMR δ: 0.90(s, 3H), 0.99(s, 3H), 1.33(d, J=6.4 Hz, 3H), 1.52(s, 6H),3.79(brs, 1H), 3.98-4.23(m, 4H), 5.43-5.50(m, 1H), 5.66(brs, 1H),5.70-5.80(m, 1H). UV λ_(max) nm: 270, 281, 293.

Example 96 Preparation of1α,3β-dihydroxy-20(S)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene(83.0 mg, 0.108 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a pale yellow oil (15.9 mg, 34%).

IR(neat): 3400, 2950, 2850, 1460, 1370, 1230, 1150, 1050 cm⁻¹. ¹H NMR δ:0.89(s, 3H), 0.99(s, 3H), 1.33(s, 6H), 3.71-4.12(m, 5H), 5.42-5.51(m,1H), 5.63(brs, 1H), 5.66-5.92(m, 3H). UV λ_(max) nm: 270, 281, 293

Example 97 Preparation of1α,3β-dihydroxy-20(S)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene(78.0 mg, 0.101 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a colorless oil (32.0 mg, 74%).

IR(neat): 3400, 2960, 2850, 1460, 1375, 1260, 1150, 1050 cm⁻¹. ¹H NMR δ:0.89(s, 3H), 0.97(s, 3H), 1.34(s, 6H), 3.76(brs, 1H), 3.96-4.24(m, 4H),5.35-5.51(m, 2H), 5.59-5.78(m, 3H). UV λ_(max) nm: 270, 281, 293.

Example 98 Preparation of1α,3β-dihydroxy-20(S)-(4-ethyl-4-hydroxy-2-hexynyloxy)pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)pregna-5,7,16-triene(79.0 mg, 0.0991 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a colorless oil (43.5 mg, 96%).

IR(neat): 3400, 2960, 2930, 2850, 1460, 1370, 1260, 1195, 1150, 1050cm⁻¹. ¹H NMR δ: 0.90(s, 3H), 0.99(s, 3H), 1.03(t, J=7.8 Hz, 6H), 1.33(d,J=6.6 Hz, 3H), 3.79(brs, 1H), 4.02-4.31(m, 4H), 5.43-5.52(m, 1H),5.66(brs, 1H), 5.72-5.80(m, 1H). MS m/z: 454(M⁺), 263(100%). UV λ_(max)nm: 270, 281, 293.

Example 99 Preparation of1α,3β-dihydroxy-20(S)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene(84.0 mg, 0.105 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a colorless oil (37.3 mg, 78%).

IR(neat): 3400, 2960, 2925, 2850, 1460, 1371, 1255, 1200, 1150, 1055cm⁻¹. ¹H NMR δ: 0.87(t, J=7.4 Hz, 6H), 0.89(s, 3H), 0.98(s, 3H), 1.32(d,J=6.6 Hz, 3H), 1.55(q, J=7.4 Hz, 4H), 3.78(brs, 1H), 3.86(dd, J=12.6,5.3 Hz, 1H), 3.94-4.09(m, 3H), 5.41-5.51(m, 1H), 5.58-5.73(m, 4H). UVλ_(max) nm: 270, 281, 293.

Example 100 Preparation of1α,3β-dihydroxy-20(S)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene(81.3 mg, 0.102 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a pale yellow oil (44.0 mg, 94%).

IR(neat): 3400, 2965, 2930, 2850, 1460, 1370, 1275, 1150, 1050 cm⁻¹. ¹HNMR δ: 0.89(s, 3H), 0.90(t, J=7.4 Hz, 6H), 0.98(s, 3H), 1.33(d, J=6.6Hz, 3H), 1.54(q, J=7.4 Hz, 4H), 3.78(brs, 1H), 3.98-4.24(m, 4H),5.37-5.49(m, 2H), 5.54-5.68(m, 2H), 5.71-5.78(m, 1H). UV λ_(max) nm:270, 281, 293.

Example 101 Preparation of1α,3β-dihydroxy-20(R)-(4-hydroxy-4-methyl-2-pentynyloxy)pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy)pregna-5,7,16-triene(74.1 mg, 0.0963 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a pale yellow oil (21.0 mg, 51%).

IR(neat): 3400, 2970, 2920, 2850, 1450, 1370, 1230, 1160, 1050 cm⁻¹. ¹HNMR δ: 0.85(s, 3H), 0.97(s, 3H), 1.35(d, J=6.4 Hz, 3H), 1.52(s, 6H),3.78(m, 1H), 5.41-5.50(m, 1H), 5.64-5.78(m, 2H). UV λ_(max) nm: 270,281, 293.

Example 102 Preparation of1α,3β-dihydroxy-20(R)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(E)-(4-methyl-4-triethylsilyloxy-2-pentenyloxy)}pregna-5,7,16-triene(71.0 mg, 0.0920 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a colorless oil (34.0 mg, 86%).

IR(neat): 3400, 2960, 2925, 2850, 1460, 1370, 1240, 1150, 1055 cm⁻¹. ¹HNMR δ: 0.85(s, 3H), 0.97(s, 3H), 1.32(s, 6H), 3.77(brs, 1H),3.85-4.16(m, 4H), 5.40-5.50(m, 1H), 5.61-5.91(m, 4H). UV λ_(max) nm:270, 281, 293.

Example 103 Preparation of1α,3β-dihydroxy-20(R)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(Z)-(4-methyl-4-triethyl-silyloxy-2-pentenyloxy)}pregna-5,7,16-triene(67.9 mg, 0.0880 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a white solid (32.0 mg, 85%).

IR(KBr): 3400, 2960, 2920, 2850, 1460, 1370, 1200, 1170, 1135, 1080,1060, 1035 cm⁻¹. ¹H NMR(CDCl₃/CD₃OD) δ: 0.86(s, 3H), 0.96(s, 3H),1.33(s, 6H), 1.37(d, J=6.6 Hz, 3H), 3.74(brs, 1H), 3.90-4.27(m, 4H),5.36-5.50(m, 2H), 5.55-5.76(m, 3H). UV λ_(max) nm: 270, 281, 293.

Example 104 Preparation of1α,3β-dihydroxy-20(R)-(4-ethyl-4-hydroxy-2-hexynyloxy)pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-(4-ethyl-4-triethylsilyloxy-2-hexynyloxy)pregna-5,7,16-triene(58.2 mg, 0.0730 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a colorless oil (33.5 mg, 100%).

IR(neat): 3400, 2960, 2930, 2850, 1460, 1370, 1325, 1260, 1195, 1150,1060, 1035 cm⁻¹. ¹H NMR δ: 0.85(s, 3H), 0.98(s, 3H), 1.03(t, J=7.4 Hz,6H), 1.34(d, J=6.6 Hz, 3H), 3.78(brs, 1H), 4.00-4.32(m, 4H),5.41-5.50(m, 1H), 5.68(brs, 1H), 5.71-5.80(m, 1H). UV λ_(max) nm: 270,281, 293.

Example 105 Preparation of1α,3β-dihydroxy-20(R)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(E)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene(60.3 mg, 0.0754 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=20:80:1, developed once) to givethe title compound as a pale yellow oil (14.5 mg, 42%).

IR(neat): 3400, 2960, 2930, 2850, 1460, 1375, 1330, 1270, 1150, 1060,1035 cm⁻¹. ¹H NMR δ: 0.86(s, 3H), 0.86(t, J=7.3 Hz, 6H), 0.98(s, 3H),1.33(d, J=6.6 Hz, 3H), 1.55(q, J=7.6 Hz, 4H), 3.78(brs, 1H),3.91-4.20(m, 4H), 5.42-5.52(m, 1H), 5.58-5.82(m, 4H). UV λ_(max) nm:270, 281, 293.

Example 106 Preparation of1α,3β-dihydroxy-20(R)-{(z)-(4-ethyl-4-hydroxy-2-hexenyloxy)}pregna-5,7,16-triene

By the same procedure as in Example 9,1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{(Z)-(4-ethyl-4-triethylsilyloxy-2-hexenyloxy)}pregna-5,7,16-triene(82.0 mg, 0.103 mmol), tetrahydrofuran (3 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) werereacted (heating under reflux for 5.5 hours) and worked up, and then theresidue was purified by preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate: ethanol=20:80:1, developed once) to givethe title compound as a white solid (46.1 mg, 98%).

IR(KBr): 3400, 2960, 2930, 2850, 1460, 1370, 1325, 1270, 1250, 1200,1150, 1060, cm⁻¹. ¹H NMR δ: 0.86(s, 3H), 0.90(t, J=7.4 Hz, 6H), 0.98(s,3H), 1.36(d, J=6.4 Hz, 3H), 1.54(q, J=7.4 Hz, 4H), 3.77(brs, 1H),3.99-4.22(m, 4H), 5.35-5.49(m, 2H), 5.55-5.70(m, 2H), 5.71-5.79(m, 1H).UV λ_(max) nm: 270, 281, 293.

Example 107 Preparation of1α,3β-dihydroxy-20(S)-(4-hydroxy-4-methyl-2-pentynyloxy)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-(4-hydroxy-4-methyl-2-pentynyloxy)pregna-5,7,16-triene(13.0 mg, 0.0305 mmol) and ethanol (200 ml), the reaction (irradiationfor 2.5 minutes and heating under reflux for 1.5 hours) and work up wereperformed by the same procedure as in Example 15, and then the residuewas purified by preparative thin layer chromatography (0.5 mm×1,hexane:ethyl acetate:ethanol=8:12:1, developed twice, 0.25 mm×1,dichloromethane:ethyl acetate:ethanol=10:10:1, developed twice, thendichloromethane:ethanol=19:1, developed three times) to give the titlecompound as a colorless oil (0.758 mg, 5.8%).

IR(neat): 3369, 2929, 2852, 1442, 1369, 1234, 1167, 1060 cm⁻¹. ¹H NMR δ:0.79(s, 3H), 1.33(d, J=6.6 Hz, 3H), 1.52(s, 6H), 4.03(d, J=15.4 Hz, 1H),4.14(m, 1H), 4.15(d, J=15.4 Hz, 1H), 4.19-4.30(m, 1H), 4.41-4.51(m, 1H),5.02(brs, 1H), 5.34(brs, 1H), 5.62(brs, 1H), 6.11(d, J=11.2 Hz, 1H),6.38(d, J=11.2 Hz, 1H). MS m/z: 367(M⁺-C(CH₃)₂OH), 129(100%). UV λ_(max)nm: 264.

Example 108 Preparation of1α,3β-dihydroxy-20(S)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)}pregna-5,7,16-triene(14.5 mg, 0.0338 mmol) and ethanol (200 ml), the reaction (irradiationfor 2.5 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1,dichloromethane:ethyl acetate:ethanol=10:10:1, developed twice, then0.25 mm×1, dichloromethane:ethanol=18:1, developed three times) to givethe title compound as a colorless oil (1.41 mg, 9.7%).

IR(neat): 3400, 2929, 2850, 1446, 1369, 1220, 1153, 1101, 1055 cm⁻¹. ¹HNMR δ: 0.79(s, 3H), 1.33(s, 6H), 3.81(dd, J=6.3, 5.6 Hz, 1H),3.89-4.04(m, 2H), 4.17-4.30(m, 1H), 4.38-4.50(m, 1H), 5.02(brs, 1H),5.34(brs, 1H), 5.59(brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.27(d, J=11.2 Hz,1H). MS m/z: 410(M⁺-H₂O), 134(100%). UV λ_(max) nm: 264.

Example 109 Preparation of1α,3β-dlhydroxy-20(S)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)}pregna-5,7,16-triene(30.0 mg, 0.0700 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.5 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=16:1, developed three times) to give the titlecompound as a colorless oil (3.04 mg, 10%).

IR(neat): 3369, 2972, 2929, 2850, 1446, 1371, 1169, 1055 cm⁻¹. ¹H NMR δ:0.78(s, 3H), 1.34(s, 6H), 2.54-2.68(m, 1H), 2.75-2.88(m, 1H),3.95-4.30(m, 4H), 4.38-4.50(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H),5.44(dt, J=12.2, 5.6 Hz, 1H), 5.58-5.70 (m, 2H), 6.11 (d, J=11.2 Hz,1H), 6.37 (d, J=11.2 Hz, 1H). UV λ_(max) nm: 263.

Example 110 Preparation of1α,3β-dihydroxy-20(S)-(4-ethyl-4-hydroxy-2-hexynyloxy)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-(4-ethyl-4-hydroxy-2-hexynyloxy)pregna-5,7,16-triene(40.0 mg, 0.0880 mmol) and ethanol (200 ml), the reaction (irradiationfor 2.5 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=19:1, developed three times) to give the titlecompound as a colorless oil (2.76 mg, 6.9%).

IR(neat): 3369, 2970, 2931, 2850, 1442, 1369, 1263, 1182, 1146, 1057cm⁻¹. ¹H NMR δ: 0.79(s, 3H), 1.03(t, J=7.4 Hz, 6H), 1.32(d, J=6.3 Hz,3H), 2.55-2.65(m, 1H), 2.77-2.88(m, 1H), 4.06(d, J=15.5 Hz, 1H),4.14-4.31(m, 3H), 4.38-4.53(m, 1H), 5.02(brs, 1H), 5.34(brs, 1H),5.61(brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). UVλ_(max) nm: 264.

Example 111 Preparation of1α,3β-dihydroxy-20(S)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)}pregna-5,7,16-triene(35.0 mg, 0.0766 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.5 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=16:1, developed three times) to give the titlecompound as a colorless oil (3.94 mg, 11%).

IR(neat): 3400, 2968, 2931, 2850, 1446, 1369, 1101, 1055 cm⁻¹. ¹H NMR δ:0.79(s, 3H), 0.86(t, J=7.4 Hz, 6H), 2.55-2.68(m, 1H), 2.77-2.89(m, 1H),3.86(dd, J=12.4, 5.4 Hz, 1H), 3.93-4.06(m, 2H), 4.18-4.31(m, 1H),4.39-4.52(m, 1H), 5.02(brs, 1H), 5.34(brs, 1H), 5.58(brs, 1H), 6.11(d,J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). MS m/z: 456(M⁺), 134(100%). UVλ_(max) nm: 263.

Example 112 Preparation of1α,3β-dihydroxy-20(S)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)}pregna-5,7,16-triene(41.0 mg, 0.0898 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.75 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=16:1, developed three times) to give the titlecompound as a colorless oil (1.58 mg, 3.9%).

IR(neat): 3400, 2968, 2929, 2850, 1448, 1371, 1055 cm⁻¹. ¹H NMR δ:0.78(s, 3H), 0.90(t, J=7.4 Hz, 3H), 0.91(t, J=7.4 Hz, 3H), 1.34(d, J=6.3Hz, 3H), 2.55-2.65(m, 1H), 2.78-2.88(m, 1H), 3.95-4.31(m, 4H),4.39-4.51(m, 1H), 5.01(brs, 1H), 5.34(brs, 1H), 5.42(d, J=12.5 Hz, 1H),5.55-5.69(m, 2H), 6.11(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). UVλ_(max) nm: 263.

Example 113 Preparation of1α,3β-dihydroxy-20(R)-(4-hydroxy-4-methyl-2-pentynyloxy)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(R)-(4-hydroxy-4-methyl-2-pentynyloxy)pregna-5,7,16-triene(20.0 mg, 0.0469 mmol) and ethanol (200 ml), the reaction (irradiationfor 3 minutes and heating under reflux for 2 hours) was performed by thesame procedure as in Example 15, and then the residue was purified bypreparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, 0.25 mm×1, dichloromethaneethyl acetate ethanol=10:10:1, developed twice, then dichloromethaneethanol=19:1, developed three times) to give the title compound as acolorless oil (1.19 mg, 5.9%).

IR(neat): 3400, 2976, 2929, 2852, 1444, 1373, 1234, 1167, 1063 cm⁻¹. ¹HNMR δ: 0.75(s, 3H), 1.33(d, J=6.3 Hz, 3H), 1.52 (s, 6H), 2.55-2.66(m,1H), 2.76-2.86(m, 1H), 4.03-4.31(m, 4H), 4.40-4.50(m, 1H), 5.01(brs,1H), 5.34(brs, 1H), 5.56(brs, 1H), 6.11(d, J=11.2 Hz, 1H), 6.37(d,J=11.2 Hz, 1H). UV λ_(max) nm: 264.

Example 114 Preparation of1α,3β-dihydroxy-20(R)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{(E)-(4-hydroxy-4-methyl-2-pentenyloxy)}pregna-5,7,16-triene(31.8 mg, 0.0742 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.5 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=10:10:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=18:1, developed three times) to give the titlecompound as a colorless oil (3.03 mg, 9.5%).

IR(neat): 3390, 2972, 2931, 2850, 1448, 1371, 1217, 1153, 1095, 1057cm⁻¹. ¹H NMR δ: 0.75(s, 3H), 1.33(s, 6H), 2.56-2.68(m, 1H), 2.78-2.88(m,1H), 3.85-4.08(m, 3H), 4.18-4.30(m, 1H), 4.39-5.00(m, 1H), 5.01(brs,1H), 5.34(brs, 1H), 5.62(brs, 1H), 5.73(dt, J=15.8, 5.3 Hz, 1H), 5.85(d,J=15.8 Hz, 1H), 6.11(d, J=11.2 Hz, 1H), 6.38(d, J=11.2 Hz, 1H). UVλ_(max) nm: 263.

Example 115 Preparation of1α,3β-dihydroxy-20(R)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(R)-{(Z)-(4-hydroxy-4-methyl-2-pentenyloxy)}pregna-5,7,16-triene(30.0 mg, 0.0700 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.5 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=16:1, developed three times) to give the titlecompound as a colorless oil (3.04 mg, 10%).

IR(neat): 3350, 2972, 2929, 2850, 1448, 1371, 1167, 1063 cm⁻¹. ¹H NMR δ:0.75(s, 3H), 1.34(s, 6H), 2.55-2.67(m, 1H), 2.75-2.87(m, 1H), 4.06(q,J=6.3 Hz, 1H), 4.11-4.30(m, 3H), 4.38-4.50(m, 1H), 5.01(brs, 1H),5.34(brs, 1H), 5.45(dt, J=12.5, 5.3 Hz, 1H), 5.58(m, 2H), 6.01(d, J=11.2Hz, 1H), 6.37(d, J=11.2 Hz, 1H). UV λ_(max) nm: 263.

Example 116 Preparation of1α,3β-dihydroxy-20(R)-(4-ethyl-4-hydroxy-2-hexynyloxy)-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(R)-(4-ethyl-4-hydroxy-2-hexynyloxy)pregna-5,7,16-triene(30.8 mg, 0.0677 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.5 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=19:1, developed three times) to give the titlecompound as a colorless oil (1.83 mg, 5.9%).

IR(neat): 3390, 2970, 2933, 2852, 1450, 1371, 1265, 1146, 1061 cm⁻¹. ¹HNMR δ: 0.75(s, 3H), 1.03(t, J=7.4 Hz, 6H), 1.33(d, J=6.6 Hz, 3H),2.56-2.65(m, 1H), 2.75-2.85(m, 1H), 4.08-4.29(m, 4H), 4.39-4.53(m, 1H),5.01(brs, 1H), 5.34(brs, 1H), 5.64(brs, 1H), 6.10(d, J=11.2 Hz, 1H),6.38(d, J=11.2 Hz, 1H). UV λ_(max) nm: 264.

Example 117 Preparation of1α,3β-dihydroxy-20(R)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(R)-{(E)-(4-ethyl-4-hydroxy-2-hexenyloxy)}pregna-5,7,16-triene(13.0 mg, 0.0285 mmol) and ethanol (200 ml), the reaction (irradiationfor 2.5 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=16:1, developed three times) to give the titlecompound as a colorless oil (0.888 mg, 6.8%).

IR(neat): 3378, 2964, 2925, 2852, 1452, 1385, 1057 cm⁻¹. ¹H NMR δ:0.75(s, 3H), 0.86(t, J=7.4 Hz, 6H), 1.32(d, J=6.6 Hz, 3H), 2.55-2.66(m,1H), 2.76-2.87(m, 1H), 3.90-4.10(m, 3H), 4.18-4.31(m, 1H), 4.39-4.51(m,1H), 5.02(brs, 1H), 5.34(brs, 1H), 5.57-5.81(m, 3H), 6.11(d, J=11.2 Hz,1H), 6.38(d, J=11.2 Hz, 1H). UV λ_(max) nm: 263.

Example 118 Preparation of1α,3β-dihydroxy-20(R)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)}-1-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(R)-{(Z)-(4-ethyl-4-hydroxy-2-hexenyloxy)}pregna-5,7,16-triene(42.1 mg, 0.0922 mmol) and ethanol (200 ml), the reaction (irradiationfor 3.75 minutes and heating under reflux for 2 hours) was performed bythe same procedure as in Example 15, and then the residue was purifiedby preparative thin layer chromatography (0.5 mm×1, hexane:ethylacetate:ethanol=8:12:1, developed twice, then 0.25 mm×1,dichloromethane:ethanol=16:1, developed three times) to give the titlecompound as a colorless oil (2.09 mg, 5.0%).

IR(neat): 3400, 2968, 2931, 2852, 1456, 1371, 1059 cm⁻¹. ¹H NMR δ:0.75(s, 3H), 0.90(t, J=7.4 Hz, 6H), 1.34(d, J=6.6 Hz, 3H), 2.55-2.66(m,1H), 2.73-2.89(m, 1H), 3.98-4.31(m, 4H), 4.39-4.51(m, 1H), 5.01(brs,1H), 5.34(brs, 1H), 5.41(d, J=12.5 Hz, 1H), 5.55-5.71(m, 2H), 6.10(d,J=11.2 Hz, 1H), 6.37(d, J=11.2 Hz, 1H). UV λ_(max) nm: 263.

Example 119 Preparation of1α,3β-dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene

To a solution of1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(97.9 mg, 0.175 mmol), potassium t-butoxide (230 mg, 2.05 mmol) anddibenzo-18-crown-6 (45.0 mg, 0.125 mmol) in toluene (6 ml) was added(S)-(+)-1,2-epoxy-3-methylbutane (0.18 ml, 1.72 mmol) at roomtemperature and the mixted solution was stirred at 106° C. for one hour.The reaction solution was diluted with diethyl ether and washed withbrine, and then the organic layer was dried over magnesium sulfate. Thesolvent was distilled off under reduced pressure and the resultingresidue was separated by preparative thin layer chromatography (0.5mm×4, hexane:dichloromethane:ethyl acetate=45:5:2, developed threetimes) to give a fraction containing1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{2(S)-hydroxy-3-methyl-butyloxy}pregna-5,7,16-triene(67.5 mg). An aliquot of 52.6 mg was dissolved in tetrahydrofuran (1.5ml) and stirred with 1M tetra-n-butylammonium fluoride solution intetrahydrofuran (0.5 ml) under the condition of an outer temperature of71° C. for 10 hours. After completion of the reaction, the reactionsolution was diluted with ethyl acetate and washed with 1N hydrochloricacid, saturated aqueous sodium bicarbonate solution and brinesuccessively, and the organic layer was dried over magnesium sulfate.The solvent was distilled off under reduced pressure and the resultingresidue was purified by preparative thin layer chromatography (0.25mm×2, dichloromethane:ethanol 15:1, developed twice) to give the titlecompound as a colorless oil (20.6 mg, 36%).

IR(neat): 3416, 2924, 1462, 1370, 1056, 1196 cm⁻¹. ¹H NMR δ: 0.88(s,3H), 0.90(d, J=6.9 Hz, 3H), 0.97(s, 3H), 1.31(d, J=6.6 Hz, 3H),2.72-2.86(m, 1H), 3.10-3.24(m, 1H), 3.39-3.53(m, 2H), 3.77(brs, 1H),3.96(q, J=6.6 Hz, 1H), 4.00-4.16(m, 1H), 5.40-5.49(m, 1H), 5.60(s, 1H),5.68-5.80(m, 1H). MS m/z: 312(M⁺-HOCH₂CH(OH) ^(i)Pr), 223(100%). UVλ_(max) nm: 269, 281, 292.

Example 120 Preparation of1α,3β-dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene

Using1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-hydroxypregna-5,7,16-triene(71.5 mg, 0.128 mmol), potassium t-butoxide (170 mg, 1.52 mmol),dibenzo-18-crown-6 (32.0 mg, 0.0888 mmol), toluene (4.5 ml) and(R)-(−)-1,2-epoxy-3-methylbutane (0.13 ml, 1.24 mmol), alkylationreacion (108° C., 1 hour) and work up were performed by the sameprocedure as in Example 119, and then the residue was separated bypreparative thin layer chromatography (0.5 mm×3,hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) togive a fraction containing1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene(26.8 mg). This was deprotected with tetrahydrofuran (1 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.4 ml)(reaction temperature 74° C., reaction period 12 hours) and worked up bythe same procedure as in Example 119, and then the residue was purifiedby preparative thin layer chromatography (0.25 mm×1,dichloromethane:ethanol=15:1, developed twice) to give the titlecompound as a colorless oil (12.0 mg, 23%).

IR(neat): 3420, 2924, 1460, 1368, 1056 cm⁻¹. ¹H NMR δ: 0.89(s, 3H),0.89(d, J=6.6 Hz, 3H), 0.98(s, 3H), 1.32(d, J=6.6 Hz, 3H), 2.49-2.62(m,1H), 2.72-2.87(m, 1H), 3.26-3.54(m, 3H), 3.77(brs, 1H), 3.93-4.18(m,2H), 5.41-5.50(m, 1H), 5.63(s, 1H), 5.70-5.80(m, 1H). MS m/z:312(M⁺-HOCH₂CH(OH) ^(i)Pr, 100% ). UV λ_(max) nm: 269, 280, 292.

Example 121 Preparation of1α,3β-dihydroxy-20(R)-{2(S)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene

Using1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene(79.0 mg, 0.141 mmol), potassium t-butoxide (190 mg, 1.69 mmol),dibenzo-18-crown-6 (25.0 mg, 0.0694 mmol), toluene (4.5 ml) and(S)-(+)-1,2-epoxy-3-methylbutane (0.15 ml, 1.43 mmol), alkylationreaction (108° C., 1 hour) and work up were performed by the sameprocedure as in Example 119, and then the residue was separated bypreparative thin layer chromatography (0.5 mm×3,hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) togive a fraction containing1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{2(S)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene(27.8 mg). This was deprotected with tetrahydrofuran (1 ml) and 1Mtetra-n-butylammonium fluoride solution in tetrahydrofuran (0.25 ml)(reaction temperature 76° C., reaction period 13 hours) and worked up bythe same procedure as in Example 119, and then the residue was purifiedby preparative thin layer chromatography (0.25 mm×1,dichloromethane:ethanol 15:1, developed twice) to give the titlecompound as a colorless oil (11.0 mg, 19%).

IR(neat): 3416, 3036, 2928, 1462, 1370, 1270, 1196, 1056 cm⁻¹. ¹H NMR δ:0.84(s, 3H), 0.90(d, J=6.9 Hz, 3H), 0.97(s, 3H), 1.34(d, J=6.6 Hz, 3H),2.72-2.88(m, 1H), 3.19-3.34(m, 1H), 3.40-3.60(m, 2H), 3.77(brs, 1H),3.93-4.16(m, 2H), 5.40-5.50 (m, 1H), 5.67(s, 1H), 5.71-5.80 (m, 1H). MSm/z: 312 (M⁺-HOCH₂CH(OH) ^(i)Pr, 100%). UV λ_(max) nm: 270, 281, 293.

Example 122 Preparation of1α,3β-dihydroxy-20(R)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene

Using1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-hydroxypregna-5,7,16-triene(69.7 mg, 0.125 mmol), potassium t-butoxide (170 mg, 1.52 mmol),dibenzo-18-crown-6 (22.0 mg, 0.0610 mmol), toluene (4 ml) and(R)-(−)-1,2-epoxy-3-methylbutane (0.13 ml, 1.24 mmol), alkylationreaction (109° C., 1 hour) and work up were performed by the sameprocedure as in Example 119, and then the residue was separated bypreparative thin layer chromatography (0.5 mm×3,hexane:dichloromethane:ethyl acetate=45:5:2, developed three times) togive a fraction containing1α,3β-bis(tert-butyldimethylsilyloxy)-20(R)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene(23.6 mg). An aliquot of 21.1 mg was deprotected with tetrahydrofuran (1ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran(0.2 ml) (reaction temperature 76° C., reaction period 13 hours) andworked up by the same procedure as in Example 119, and then the residuewas purified by preparative thin layer chromatography (0.25 mm×1,dichloromethane:ethanol=15:1, developed twice) to give the titlecompound as a colorless oil (9.4 mg, 20%).

IR(neat): 3404, 2960, 2928, 1462, 1370, 1272, 1196, 1056 cm⁻¹. ¹H NMR δ:0.85(s, 3H), 0.90(d, J=6.9 Hz, 3H), 0.98(s, 3H), 1.33(d, J=6.3 Hz, 3H),2.49-2.61(m, 1H), 2.74-2.87(m, 1H), 3.21-3.35(m, 1H), 3.39-3.56(m, 2H),3.78(brs, 1H), 3.93-4.15(m, 2H), 5.40-5.50(m, 1H), 5.65(s, 1H),5.70-5.81(m, 1H). MS m/z: 312(M⁺-HOCH₂CH(OH) ^(i)Pr, 100%). UV λ_(max)nm: 269, 281, 293.

Example 123 Preparation of1α,3β-dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene(9.7 mg, 0.0233 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 1 minute and 40seconds, and heating under reflux for 2 hours), and then the residue waspurified by preparative thin layer chromatography (0.25 mm×1,dichloromethane:ethanol=20:1, developed twice, then 0.25 mm×0.5,hexane:ethyl acetate:ethanol=10:5:1, developed twice) to give the titlecompound as a colorless oil (1.06 mg, 11%).

IR(neat): 3400, 2928, 1444, 1368, 1056 cm⁻¹. ¹H NMR δ: 0.78(s, 3H),0.90(d, J=6.9 Hz, 3H), 0.96(d, J=6.9 Hz, 3H), 1.31(d, J=6.6 Hz, 3H),2.53-2.68(m, 1H), 2.76-2.90(m, 1H), 3.09-3.24(m, 1H), 3.40-3.55(m, 2H),3.88-4.01(m, 1H), 4.18-4.30(m, 1H), 4.40-4.50(m, 1H), 5.01(s, 1H),5.34(s, 1H), 5.57(s, 1H), 6.10(d, J=11.4 Hz, 1H), 6.37(d, J=11.4 Hz,1H). MS m/z: 312(M⁺-HOCH₂CH(OH) ^(i)Pr), 149(100%). UV λ_(max) nm: 262.

Example 124 Preparation of1α,3β-dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene(12.0 mg, 0.0288 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 1 minute and 40seconds, and heating under reflux for 2 hours), and then the residue waspurified by preparative thin layer chromatography (0.25 mm×1,hexane:ethyl acetate:ethanol=10:5:1, developed once, then 0.25 mm×0.5,dichloromethane:ethanol=30:1, developed twice, thendichloromethane:ethanol=10:1, developed twice) to give the titlecompound as a colorless oil (1.45 mg, 12%).

IR(neat): 3400, 2928, 1444, 1370, 1056 cm⁻¹. ¹H NMR δ: 0.78(s, 3H),0.89(d, J=6.9 Hz, 3H), 0.97(d, J=6.9 Hz, 3H), 1.31(d, J=6.6 Hz, 3H),2.54-2.67(m, 1H), 2.74-2.90(m, 1H), 3.25-3.53(m, 3H), 3.95(q, J=6.6 Hz,1H), 4.19-4.32(m, 1H), 4.38-4.51(m, 1H), 5.01(s, 1H), 5.34(s, 1H),5.58(s, 1H), 6.11(d, J=11.4 Hz, 1H), 6.37(d, J=11.4 Hz, 1H). MS m/z:312(M⁺-HOCH₂CH(OH) ^(i)Pr), 149 (100%). UV λ_(max) nm: 263.

Example 125 Preparation of1α,3β-dihydroxy-20(R)-{2(S)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(R)-{2(S)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene(9.9 mg, 0.0238 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 1 minute and 40seconds, and heating under reflux for 2 hours), and then the residue waspurified by preparative thin layer chromatography (0.25 mm×1,hexane:ethyl acetate:ethanol=10:5:1, developed twice, then 0.25 mm×0.5,dichloromethane:ethanol=15:1, developed twice) to give the titlecompound as a colorless oil (0.786 mg, 7.9%).

IR(neat): 3392, 2928, 1452, 1370, 1264, 1056 cm⁻¹. ¹H NMR δ: 0.74(s,3H), 0.90(d, J=6.6 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 1.33(d, J=6.3 Hz,3H), 2.55-2.68(m, 1H), 2.77-2.90(m, 1H), 3.21-3.34(m, 1H), 3.41-3.56(m,2H), 3.98(q, J=6.3 Hz, 1H), 4.18-4.31(m, 1H), 4.38-4.51(m, 1H), 5.01(s,1H), 5.34(s, 1H), 5.63(s, 1H), 6.10(d, J=11.4 Hz, 1H), 6.37(d, J=11.4Hz, 1H). MS m/z: 312(M⁺-HOCH₂CH(OH) ^(i)Pr), 149(100%). UV λ_(max) nm:262.

Example 126 Preparation of1α,3β-dihydroxy-20(R)-{2(R)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene

Using1α,3β-dihydroxy-20(R)-{2(R)-hydroxy-3-methylbutyloxy}pregna-5,7,16-triene(8.5 mg, 0.0204 mmol) and ethanol (200 ml), the reaction was performedby the same procedure as in Example 15 (irradiation for 1 minute and 40seconds, and heating under reflux for 2 hours), and then the residue waspurified by preparative thin layer chromatography (0.25 mm×1,dichloromethane:ethanol=15:1, developed twice, then 0.25 mm×0.5,hexane:ethyl acetate:ethanol=10:5:1, developed twice) to give the titlecompound as a colorless oil (0.400 mg, 4.7%).

IR(neat): 3416, 2924, 1452, 1370, 1262, 1066 cm⁻¹. ¹H NMR δ: 0.75 (s,3H), 0.91(d, J=6.6 Hz, 3H), 0.97(d, J=6.6 Hz, 3H), 1.32(d, J=6.3 Hz,3H), 2.55-2.67(m, 1H), 2.77-2.88(m, 1H), 3.21-3.33(m, 1H), 3.36-3.57(m,2H), 3.92-4.06(m, 1H), 4.19-4.30(m, 1H), 4.40-4.50(m, 1H), 5.01(s, 1H),5.34(s, 1H), 5.60(s, 1H), 6.10(d, J=11.4 Hz, 1H), 6.37(d, J=11.4 Hz,1H). UV λ_(max) nm: 260.

The following test examples report activities of Compound 1(1α,3β-dihydroxy-20(S)-(3-hydroxy-3-methyl-butylthio)-9,10-secopregna-5,7,10(19),16-tetraene),Compound 2(1α,3β-dihydroxy-20(R)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene),Compound 3(1α,3β-dihydroxy-20(R)-(4-hydroxy-4-methyl-2-pentynylthio)-9,10-secopregna-5,7,10(19),16-tetraene),Compound 4(1α,3β-dihydroxy-20(R)-(4-ethyl-4-hydroxy-2-hexynylthio)-9,10-secopregna-5,7,10(19),16-tetraene),Compound 5(1α,3β-dihydroxy-20(R)-((E)-4-hydroxy-4-methyl-2-pentenylthio)-9,10-secopregna-5,7,10(19),16-tetraene)and Compound 6(1α,3β-dihydroxy-20(R)-((E)-4-ethyl-4-hydroxy-2-hexenylthio)-9,10-secopregna-5,7,10(19),16-tetraene).

Test Example 1

At hour 24 after an activated vitamin D₃ or each vitamin D₃ derivativedissolved in phosphate buffer was intravenously administered to 8-weekold male ddY mice at a dose of 30 μg/kg, the ionized calcium level inblood was determined. Experiments were run on 5 examples for each groupand the results were expressed as average±standard deviation. Thecalcemic activity of the activated vitamin D₃ and each vitamin D₃derivative was evaluated in comparison with that of a control group towhich had been administered the same amount of phosphate buffer alone.The results are shown in FIGS. 1 to 3. The significance of differenceswas determined using Dunnett's T test, and the symbols *, ** and *** inthe figures mean significant differences at the probability levels of5%, 1% and 0.1%, respectively.

Test Example 2

HL-60 cells were subcultured in RPMI-1640 medium containing 10% fetalbovine serum and 20 μg/ml gentamicin under 5% CO₂ at 37° C.Differentiation-inducing activity was evaluated as follows. At first, a24-well plate was inoculated with 10⁵ cells on the medium containingeach test compound at various concentrations and incubated for 4 daysunder the above incubation conditions. Then, the amount of superoxideproduced by stimulation of phorbol myristate acetate (PMA) wasdetermined as cytochrome C-reducing ability. Namely, culturesupernatants were removed by suction and then the cells treated witheach test compound were suspended in 1.5 ml of the reaction mixture (80μM ferricytochrome C, 500 ng/ml PMA) and incubated at 37° C. for onehour. Then, the absorbance of the culture supernatants was determined atOD 550-540 using a Hitachi dual-wavelength spectrophotometer. Theresults are shown in FIGS. 4 to 6. The concentration of reducedcytochrome C was calculated by using a molar absorption coefficient of19.1×10³ cm⁻¹.

INDUSTRIAL APPLICABILITY

Compounds of general formula (1) of the present invention are useful aspharmaceutical agents such as antitumor agents or antirheumatic agentswith weak hypercalcemic activity.

What is claimed is:
 1. A vitamin D derivative of general formula (1):

wherein X represents an oxygen or sulfur atom, R₁₁ represents asaturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group or a protected hydroxyl group, a —COR₁₂group where R₁₂ represents an alkyl, aryl or alkoxy group, or

wherein R₅ and R₆ each represent a hydrogen atom or a hydroxyl group, mrepresents an integer of 1 to 4, and n represents an integer of 0 to 2,R₂ represents —OR₉ or a hydrogen atom, and R₉ and R₁₀ may by the same ordifferent and each represents a hydrogen atom or a protecting group. 2.The vitamin D derivative of claim 1, wherein R₂ is —OR₉.
 3. The vitaminD derivative of claim 1, wherein R₁₁ is a saturated C1-C15 aliphatichydrocarbon group which may be substituted by a hydroxyl group.
 4. Thevitamin D derivative of claim 1, wherein R₁₁ is an unsaturated C2-C15aliphatic hydrocarbon group which may be substituted by a hydroxylgroup.
 5. The vitamin D derivative of claim 1, wherein R₁₁ is a group(2):

wherein R₃ and R₄ may be the same or different and each represent ahydrogen atom or a hydroxyl group, or are combined to represent ═O,provided that R₃ and R₄ can not be a hydroxyl group simultaneously, R₅and R₆ each represent a hydrogen atom or a hydroxyl group, but R₆ cannot be a hydroxyl group simultaneously with R₃ or R₄, m represents aninteger of 1 to 4, and n represents an integer of 0 to 2; or a group(3):

wherein R₅ and R₆ may be the same or different and each represent ahydrogen atom or a hydroxyl group, R₇ and R₈ each represent a hydrogenatom or are combined to represent a covalent bond, p represents aninteger of 1 to 3, and q represents an integer of 0 to
 2. 6. The vitaminD derivative of claim 1, wherein R₁₁ is a 3-hydroxy-3-methylbutyl group.7. The vitamin D derivative of claim 1, wherein the 20-position is inS-configuration.
 8. The vitamin D derivative of claim 1, wherein the20-position is in R-configuration. 9.1,3-Dihydroxy-20-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.10.1α,3β-Dihydroxy-20(S)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.11.1α,3β-Dihydroxy-20(R)-(3-hydroxy-3-methylbutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.12.1α,3β-Dihydroxy-20(R)-((E)-4-hydroxy-4-methyl-2-pentenylthio)-9,10-secopregna-5,7,10(19),16-tetraene.13.1α,3β-Dihydroxy-20(R)-((E)-4-ethyl-4-hydroxy-2-hexenylthio)-9,10-secopregna-5,7,10(19),16-tetraene.14.1α,3β-Dihydroxy-20(S)-(2-hydroxy-2-methylpropylthio)-9,10-secopregna-5,7,10(19),16-tetraene.15.1α,3β-Dihydroxy-20(R)-(2-hydroxy-2-methylpropylthio)-9,10-secopregna-5,7,10(19),16-tetraene.16.1α,3β-Dihydroxy-20(S)-{2(S)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10(19),16-tetraene.17.1α,3β-Dihydroxy-20(S)-{2(R)-hydroxy-3-methylbutyloxy}-9,10-secopregna-5,7,10,(19),16-tetraene. 18.1α,3β-dihydroxy-20(S)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.19.1α,3β-Dihydroxy-20(R)-(2-ethyl-2-hydroxybutylthio)-9,10-secopregna-5,7,10(19),16-tetraene.20. A pharmaceutical composition comprising a carrier and a vitamin Dderivative of general formula (1):

wherein X represents an oxygen or sulfur atom, R₁₁ represents asaturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group or a protected hydroxyl group, a —COR₁₂group where R₁₂ represents an alkyl, aryl or alkoxy group, or

wherein R₅ and R₆ each represent a hydrogen atom or a hydroxyl group, mrepresents an integer of 1 to 4, and n represents an integer of 0 to 2,R₂ represents —OR₉ or a hydrogen atom, and R₉ and R₁₀ may be the same ordifferent and each represent a hydrogen atom or a hydroxyl group.
 21. Aprocess for preparing a vitamin D derivative of general formula (1):

wherein X represents an oxygen or sulfur atom, R₁₁ represents asaturated or unsaturated aliphatic hydrocarbon group which may besubstituted by a hydroxyl group or a protected hydroxyl group, a —COR₁₂group where R₁₂ represents an alkyl, aryl or alkoxy group, or

wherein R₅ and R₆ each represent a hydrogen atom or a hydroxyl group, mrepresents an integer of 1 to 4, and n represents an integer of 0 to 2,R₂ represents —OR₉, or a hydrogen atom, and R₉ and R₁₀ may be the sameor different and each represents a hydrogen atom or a protecting group,which process comprises subjecting a compound of general formula (4a):

wherein X represents an oxygen or sulfur atom, R₁ represents a saturatedor unsaturated aliphatic hydrocarbon group which may be substituted byan optionally protected hydroxyl group, or a —COR₁₂ group where R₁₂represents an alkyl, aryl or alkoxy group, and R₉ and R₁₀ may be thesame or different and each represent a hydrogen atom or a protectinggroup, to photoreaction, thermal isomerization and deprotection.